Naphthalene derivatives, their production and use

ABSTRACT

A composition containing a compound of the formula: 
                         
wherein A is a nitrogen-containing heterocyclic group which may be substituted, R 1  is a hydrogen atom, hydrocarbon group which may be substituted, or monocyclic aromatic heterocyclic group which may be substituted, R 2  is a hydrogen atom or a lower alkyl group which may be substituted, R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are independently a hydrogen atom, a hydrocarbon group which may be substituted, a hydroxy group which may be substituted, a thiol group which may be substituted, an amino group which may be substituted, an acyl group or a halogen atom, a salt thereof or a prodrug thereof has steroid C 17,20 -lyase inhibitory activity, and are useful for preventing and treating a mammal suffering from, for example, primary cancer of malignant tumor, its metastasis and recurrence thereof.

This application is a continuation of U.S. patent application Ser. No.09/673,591 filed Oct. 18, 2000, now U.S. Pat. No. 6,573,289 which wasthe National Phase filing of International Patent Application No.PCT/JP99/02143, filed 22 Apr. 1999.

TECHNICAL FIELD

The present invention relates to a medicine, especially to novelnaphthalene derivatives having steroid C_(17,20)-lyase inhibitoryactivity, or its production and pharmaceutical compositions containingthe same.

BACKGROUND ART

It is known that, in the biosynthesis of androgen in vivo, steroidC_(17,20)-lyase acts at the final stage. That is, steroidC_(17,20)-lyase converts 17-hydroxypregnenolone and17-hydroxyprogesterone derived from cholesterol todehydroepiandrosterone and androstenedione, respectively. Therefore, amedicine having steroid C_(17,20)-lyase inhibitory activity suppress theformation of androgen and estrogen which is produced from androgen, andis useful for the preventing and treating diseases whose exacerbationfactor is androgen or estrogen. As the disease whose exacerbation factoris androgen or estrogen, there may be mentioned, for example, prostatecancer, prostatic hypertrophy, virilism, hirsutism, male patternalopecia, precocious puberty, breast cancer, uterine cancer, mastopathy,uterus myoma, endometriosis, adenomyosis of uterus, polycystic ovarysyndrome, etc.

It has been already known that some steroid type compounds and somenon-steroid type compounds inhibit steroid C_(17,20)-lyase. The steroidtype compounds are disclosed in, for example, WO 92/15404,WO93/20097,EP-A 288053,EP-A 413270, etc. As non-steroid type compounds,for example, (1H-imidazol-1-yl)methyl-substituted benzimidazolederivatives are shown in Japanese Published Unexamined PatentApplication No. 85975/1989, carbazole derivatives are shown inWO94/27989 and WO96/14090, azole derivatives are shown in WO95/09157,and 1H-benzimidazole derivatives are shown in U.S. Pat. No. 5,491,161.

Heretofore, steroid C_(17,20)-lyase inhibitors which can actually beused as medicine have not been known. Thus, it has been expected theearly development of steroid C_(17,20)-lyase inhibitors which are usefulas medicine.

DISCLOSURE OF INVENTION

The present inventors have done an extensive studies so as to findsuperior steroid C_(17,20)-lyase inhibitors, and found that a compoundhaving the formula (I) which have a structure of naphthalene ring havingnitrogen-containing heterocyclic group through substituted methylenechain at 2-position unexpectedly have superior steroid C_(17,20)-lyaseinhibiting activity because of their specific structure and that thecompound has less toxicity and has good properties as medicine. Thepresent invention has been accomplished by these findings.

Thus the present invention relates to:

-   (1) A compound of the formula:

-    wherein A¹ is an imidazolyl group, a thiazolyl group, an oxazolyl    group or a pyridyl group, each of which may be substituted; R¹¹ is a    hydrogen atom, a hydrocarbon group which may be substituted; or a    monocyclic aromatic heterocyclic group which may be substituted; R²¹    is a hydrogen atom or a lower alkyl group which may be substituted;    R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are independently a hydrogen atom, a    hydrocarbon group which may be substituted, a hydroxy group which    may be substituted, a thiol group which may be substituted, an amino    group which may be substituted, an acyl group or a halogen atom,    provided (1) that R¹¹ is a saturated hydrocarbon group which may be    substituted when A¹ an oxazolyl group which may be substituted or a    thiazolyl group which may be substituted, (2) that R⁷ is a hydroxy    group which may be substituted or a lower alkyl group when A¹ is a    pyridyl group and R¹¹ or R²¹ is a hydrogen atom and (3) that R²¹ is    a lower alkyl group which may be substituted when R¹¹ is a hydrogen    atom, a salt thereof;-   (2) A compound as shown in the above item (1), wherein R³, R⁴, R⁵,    R⁶, R⁷, R⁸ and R⁹ are independently a hydrogen atom, a hydrocarbon    group which may be substituted, a hydroxy group which may be    substituted, an amino group which may be substituted, an acyl group    or a halogen atom;-   (3) A compound as shown in the above item (1), wherein R³, R⁴, R⁵,    R⁶, R⁷, R⁸ and R⁹ are independently a hydrogen atom, a hydrocarbon    group which may be substituted, a hydroxy group which may be    substituted or an acyl group;-   (4) A compound as shown in the above item (1), wherein R³, R⁴, R⁵,    R⁶, R⁷, R⁸ and R⁹ are independently a hydrogen atom, a hydrocarbon    group which may be substituted, a hydroxy group which may be    substituted, or a halogen atom;-   (5) A compound as shown in the above item (1), wherein A¹ is a 4-or    5-imidazolyl group which may be substituted or a 3- or 4-pyridyl    group which may be substituted;-   (6) A compound as shown in the above item (1), wherein A¹ is a 4-or    5-imidazolyl group which may be substituted with {circle around (1)}    a C₁₋₄alkyl group unsubstituted or substituted with a C₁₋₄alkanoyl,    carboxyl, or a C₁₋₄alkoxy-carbonyl, {circle around (2)} a C₁₋₃alkoxy    group, {circle around (3)} a C₁₋₆alkanoyl {circle around (4)}    C₁₋₄alkylsulfonyl, {circle around (5)} carbamoyl, a mono- or    di-C₁₋₁₀alkyl carbamoyl group, a mono- or di-C₆₋₁₄arylcarbamoyl    group or a mono- or di-C₇₋₁₆aralkylcarbamoyl group, or {circle    around (6)} sulfamoyl, a mono- or di-C₁₋₁₀alkyl sulfamoyl group, a    mono- or di-C₆₋₁₄arylsulfamoyl group, or a mono- or di-C₇₋₁₆aralkyl    sulfamoyl group;-   (7) A compound as shown in the above item (1), wherein A¹ is a 3-or    4-pyridyl group which may be substituted with {circle around (1)} a    C₁₋₄alkyl group unsubstituted or substituted with a C₁₋₄alkanoyl,    carboxyl, or a C₁₋₄alkoxy-carbonyl, {circle around (2)} a C₁₋₃alkoxy    group, {circle around (3)} a C₁₋₆alkanoyl {circle around (4)}    C₁₋₄alkylsulfonyl, {circle around (5)} carbamoyl, a mono- or    di-C₁₋₁₀alkyl carbamoyl group, a mono- or di-C₆₋₁₄arylcarbamoyl    group or a mono- or di-C₇₋₁₆aralkylcarbamoyl group, or {circle    around (6)} sulfamoyl, a mono- or di-C₁₋₁₀alkyl sulfamoyl group, a    mono- or di-C₆₋₁₄arylsulfamoyl group, or a mono- or di-C₇₋₁₆aralkyl    sulfamoyl group;-   (8) A compound as shown in the above item (1), wherein Al is a    thiazolyl group which may be substituted;-   (9) A compound as shown in the above item (1), wherein R²¹ is a    hydrogen atom or a lower alkyl group;-   (10) A compound as shown in the above item (1), wherein R²¹ is a    hydrogen atom;-   (11) A compound as shown in the above item (1), wherein one to three    groups of R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are independently a    hydrocarbon group which may be substituted, a hydroxy group which    may be substituted, an amino group which may be substituted, an acyl    group or a halogen atom;-   (12) A compound as shown in the above item (1), wherein one to three    groups of R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are independently a    C₁₋₆alkyl group which may be substituted, a hydroxy group which may    be substituted or a C₁₋₆acyl group;-   (13) A compound as shown in the above item (1), wherein R¹¹ is a    hydrogen atom, a lower alkyl group which may be substituted, a    phenyl group which may be substituted or a pyridyl group which may    be substituted;-   (14) A compound as shown in the above item (1), wherein R¹¹ is a    hydrogen atom, a lower alkenyl group, a cyclic alkyl group, a phenyl    group, a pyridyl group, or a lower alkyl group which may be    substituted with halogen atom(s);-   (15) A compound as shown in the above item (1), wherein R¹¹ is an    C₁₋₆alkyl group and R²¹ is a hydrogen atom;-   (16) A compound as shown in the above item (1), wherein R¹¹ is an    isopropyl group and R is a hydrogen atom;-   (17) A compound as shown in the above item (1), wherein R⁷ is a    hydroxy group which may be substituted or a lower alkyl group;-   (18) A compound as shown in the above item (1), wherein R⁷ is (1) a    hydroxy group which may be substituted with a lower alkanoyl group,    a lower alkanoyloxy-lower alkyl group, a lower alkyl group, a lower    alkoxy-lower alkyl group, a lower alkyl group which may have one to    4 halogen atoms (e.g. fluorine atoms), or a benzyl group, (2) a    halogen atom, (3) a lower alkyl group which may be substituted with    a hydroxy group, (4) a lower alkynyl group, (5) a lower alkanoyl    group, (6) an amino group which may be substituted with a lower    alkanoyl group, a lower alkylaminocarbonyl group or a lower    alkylsulfonyl group, or (7) a lower alkylthio group;-   (19) A compound as shown in the above item (1), wherein R⁷ is a    lower alkyl group, a lower alkoxy group or a lower alkanoylamino    group;-   (20) A compound as shown in the above item (1), wherein R⁷ is a    methoxy group;-   (21) A compound as shown in the above item (1), wherein R⁸ is a    hydrogen atom, a lower alkyl group or a lower alkoxy group;-   (22) A compound as shown in the above item (1), wherein R⁸ is a    hydrogen atom or a lower alkoxy group;-   (23) A compound as shown in the above item (1), wherein R⁶ is (1) a    hydrogen atom, (2) a halogen atom, (3) a lower alkoxy group or (4) a    lower alkyl group which may be substituted with a hydroxy group;-   (24) A compound as shown in the above item (1), wherein R⁶ is a    hydrogen atom or a lower alkyl group;-   (25) A compound as shown in the above item (1), wherein one of R⁶,    R⁷ and R⁸ is a lower alkyl group or a lower alkoxy group;-   (26) A compound as shown in the above item (1), wherein each of R³,    R⁴, R⁵ and R⁹ is a hydrogen atom;-   (27) A prodrug of a compound shown in the above item (1);-   (28) A compound as shown in the above item (1), which is    1-(1H-imidazol-4-yl-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol,    1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol,    1-(6-methoxy-5-methylnaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol,    N-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}acetamide    or    1-(6-ethylnaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol    or a salt thereof;-   (29) A pharmaceutical composition containing a compound shown in the    above item (1) or prodrug shown in the above item (27);-   (30) A steroid C_(17,20)-lyase inhibitory composition containing a    compound of the formula:

-    wherein A is a nitrogen-containing heterocyclic group which may be    substituted, R¹ is a hydrogen atom, hydrocarbon group which may be    substituted, or monocyclic aromatic heterocyclic group which may be    substituted, R² is a hydrogen atom or a lower alkyl group which may    be substituted, R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are independently a    hydrogen atom, a hydrocarbon group which may be substituted, a    hydroxy group which may be substituted, a thiol group which may be    substituted, an amino group which may be substituted, an acyl group    or a halogen atom, a salt thereof or a prodrug thereof;-   (31) A composition as shown in the above item (30), which is an    antitumor agent;-   (32) A composition for an antitumor agent as shown in the above item    (1), wherein the antitumor agent is a treating or preventing agent    for breast cancer or prostate cancer;-   (33) A method for treating or preventing a mammal suffering from a    disease whose exacerbation factor is androgen or estrogen, which    comprises administering an effective amount of a compound of the    formula (I′), a salt thereof or a prodrug thereof, optionally    together with a pharmaceutically acceptable carrier, diluent or    excipient, to a patient suffering from the disease;-   (34) A method for treating or preventing a mammal suffering from a    disease whose exacerbation factor is androgen or estrogen, which    comprises administering an effective amount of a compound of the    formula (I), a salt thereof or a prodrug thereof, optionally    together with a pharmaceutically acceptable carrier, diluent or    excipient, to a patient suffering from the disease;-   (35) A method as shown in the above item (34) wherein the diseases    whose exacerbation factor is androgen or estrogen is a cancer;-   (36) A method as shown in the above item (34), wherein the cancer is    breast cancer or prostate cancer;-   (37) Use of a compound of the formula (I′) a salt thereof or a    prodrug thereof for the production of a pharmaceutical composition;-   (38) Use of a compound of the formula (I) a salt thereof or a    prodrug thereof for the production of a steroid C_(17,20)-lyase    inhibitory composition;-   (39) Use as shown in the above item (38), wherein the composition is    for treating or preventing a cancer;-   (40) Use as shown in the above item (38), wherein the composition is    for treating or preventing of breast cancer or prostate cancer;-   (41) A compound of the formula:

-    wherein A² is an imidazolyl group which may be substituted, R³, R⁴,    R⁵, R⁶, R⁷, R⁸ and R⁹ are independently a hydrogen atom, a    hydrocarbon group which may be substituted, a hydroxy group which    may be substituted, a thiol group which may be substituted, an amino    group which may be substituted, an amino group which may be    substituted, an acyl group or a halogen atom, or a salt thereof;-   (42) A process for producing a compound of the formula

-    wherein A³ is an imidazolyl group, a thiazolyl group or an oxazolyl    group, each of which may be substituted, R³, R⁴, R⁵, R⁶, R⁷, R⁸ and    R⁹ are independently a hydrogen atom, a hydrocarbon group which may    be substituted, a hydroxy group which may be substituted, a thiol    group which may be substituted, an amino group which may be    substituted, an acyl group or a halogen atom, and R¹² is a    hydrocarbon group which may be substituted, or a monocyclic aromatic    heterocyclic group which may be substituted, or a salt thereof,    which comprises reacting a compound of the formula:

-    wherein each symbol has the same meaning as defined above, or a    salt thereof with a compound of the formula:    R¹²-M  (III)-    wherein M is a metal or a salt thereof and R¹² has the same meaning    as defined above.

In the above formulas, as the “nitrogen-containing heterocyclic group”in the “nitrogen-containing heterocyclic group which may be substituted”shown by A, there may be mentioned a nitrogen-containing aromaticheterocyclic group, a saturated or unsaturated nitrogen-containingnon-aromatic heterocyclic group (a nitrogen-containing aliphaticheterocyclic group) having at least a nitrogen atom as the ringconstituting atoms, preferably a nitrogen-containing aromaticheterocyclic group. As the nitrogen-containing aromatic heterocyclicgroup, there may be mentioned a nitrogen-containing 5-or 6-memberedaromatic heterocyclic group such as imidazolyl, pyrrolyl, pyrazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,1,3,5-triazinyl, 1,2,4-triazinyl. Among them, imidazolyl, pyridyl,thiazolyl, oxazolyl, etc., are preferable and 4 or 5-imidazolyl groupand 3 or 4-pyridyl group are the most preferable.

In the “nitrogen-containing aromatic heterocyclic group which may besubstituted” shown by A, one to three substituents may be substituted atany position on the nitrogen-containing aromatic heterocyclic group. Asthe substituent, there may be mentioned a lower alkyl group which may besubstituted, a lower alkoxy group, an acyl group, etc. Examples of thelower alkyl which may be substituted include, an unsubstituted C₁₋₄alkylgroup such as methyl, ethyl, propyl, etc., and an C₁₋₄alkyl groupsubstituted by an C₁₋₄alkanoyl such as acetyl, propionyl, etc.,carboxyl, a C₁₋₄alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,butoxycarbonyl, etc.), etc. As the lower alkoxy group, there may bementioned, for example, a C₁₋₃alkoxy group such as methoxy, ethoxy,propoxy, isopropoxy, etc. As the acyl group, there may be mentioned, forexample, an alkanoyl group (e.g. such a C₁₋₆alkanoyl as formyl, acetyl,propionyl, etc.), an alkylsulfonyl group (e.g. such a C₁₋₄alkylsulfonylas methylsulfonyl, ethylsulfonyl, etc.), a carbamoyl group which may besubstituted (e.g. such a mono- or di-C₁₋₁₀alkyl carbamoyl group asmethylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl,etc., such a mono- or di-C₆₋₁₄arylcarbamoyl as phenylcarbamoyl,diphenylcarbamoyl, etc., such a mono- or di-C₇₋₁₆aralkylcarbamoyl groupas benzylcarbamoyl, dibenzylcarbamoyl, etc.), a sulfamoyl which may besubstituted (e.g. such a mono- or di-C₁₋₁₀alkyl sulfamoyl group asmethylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl,etc., such a mono- or di-C₆₋₁₄arylsulfamoyl group as phenylsulfamoyl,diphenylsulfamoyl, etc., such a mono- or di-C₇₋₁₆aralkyl sulfamoyl groupas benzylsulfamoyl, dibenzylsulfamoyl, etc.), etc.

The imidazolyl group which may be substituted, the thiazolyl group whichmay be substituted, the oxazolyl group which may be substituted and thepyridyl group which may be substituted, represented by A¹ have the samemeaning as the imidazolyl group which may be substituted, the thiazolylgroup which may be substituted, the oxazolyl group which may besubstituted and the pyridyl group which may be substituted,respectively, each of which may be mentioned in the definition of thenitrogen-containing heterocyclic group which may be substitutedrepresented by A. The preferable examples of A¹ is the preferableexamples mentioned in the definition of A and included in the definitionof A¹.

The imidazolyl group which may be substituted represented by A² have thesame meaning as the imidazolyl group which may be substituted which maybe mentioned in the definition of the nitrogen-containing heterocyclicgroup which may be substituted represented by A. The preferable examplesof A² is the preferable examples mentioned in the definition of A andincluded in the definition of A².

The imidazolyl group which may be substituted, the thiazolyl group whichmay be substituted and the oxazolyl group which may be substituted,represented by A³ have the same meaning as the imidazolyl group whichmay be substituted, the thiazolyl group which may be substituted and theoxazolyl group which may be substituted, which may be mentioned in thedefinition of the nitrogen-containing heterocyclic group which may besubstituted represented by A. The preferable examples of A² is thepreferable examples mentioned in the definition of A and included in thedefinition of A³.

Examples of the hydrocarbon group in the definition of “hydrocarbongroup which may be substituted” shown by R¹ include, for example, analiphatic hydrocarbon group, a cyclic hydrocarbon group, etc. Examplesof the aliphatic hydrocarbon group include, for example, a straightchain or branched aliphatic hydrocarbon group having 1 to 10 carbonatoms such as an alkyl group, an alkenyl group, etc. Among them, analkyl group is preferable. Examples of the alkyl group include, forexample, a C₁₋₁₀alkyl group, such as methyl, ethyl, n-propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,n-hexyl, isohexyl, etc. Among them, a C₁₋₆alkyl group (for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,etc.) is preferable. Examples of the alkenyl group include, for example,a C₂₋₁₀alkenyl group such as vinyl, 1-propenyl, allyl, isopropenyl,1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, sec-butenyl, etc. Amongthem, a C₂₋₆alkenyl group (for example, vinyl, 1-propenyl, allyl, etc.)is preferable. Examples of the alkynyl group include, for example, aC₂₋₁₀alkynyl group such as ethynyl, 1-propynyl, propargyl, etc. ispreferable. Among them, a C₂₋₆alkynyl group (for example, ethynyl, etc.)is preferable.

Examples of the cyclic hydrocarbon group are one having 3 to 18 carbonatoms and include, for example, an aliphatic cyclic hydrocarbon group,an aromatic hydrocarbon group, etc. Examples of the aliphatic cyclichydrocarbon group include, for example, a monocyclic or condensedpolycyclic group consisting of 3 to 10 carbon atoms. Examples of theembodiment include a cycloalkyl group, a cycloalkenyl group, a bi- ortri-cyclic condensed ring formed by condensing one of them with aC₆₋₁₄aryl group (for example, benzene, etc.), etc. Examples of thecycloalkyl group include, for example, a C₃₋₆cycloalkyl group such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Examples of thecycloalkenyl group include, for example, a C₃₋₆cycloalkenyl group suchas cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc.

Examples of the aromatic hydrocarbon group include a monocyclic aromatichydrocarbon group, a condensed polycyclic aromatic hydrocarbon group,etc., each of which is constituted with 6 to 18 carbon atoms. Examplesof the embodiment include a C₆₋₁₄aryl group such as phenyl, 1-naphthyl,2-naphthyl, 2-indenyl, 2-anthryl, etc. Among them, C₆₋₁₀aryl group (forexample, phenyl, etc.) is preferable. Examples of the substituent whichsubstitutes on the aliphatic hydrocarbon group in the definition of“hydrocarbon group which may be substituted” are not limited butinclude, for example, a halogen atom, a hydroxy group, an alkoxy group,an acyloxy group, an alkylthio group, an acylamino group, a carboxylgroup, an alkoxycarbonyl group, an oxo group, an alkylcarbonyl group, acycloalkyl group, an aryl group, an aromatic heterocyclic group, etc.These substituents may substitute on the aliphatic hydrocarbon group inchemically acceptable range. The number of the substituent is usually 1to 5 and preferably 1 to 3. When the number of substituent is more thantwo, the substituents may be the same or different from each other.

Examples of the substituent which substitutes on the cyclic hydrocarbongroup in the definition of “hydrocarbon group which may be substituted”are not limited but include, for example, a halogen atom, a hydroxygroup, an alkoxy group, an acyloxy group, an alkylthio group, analkylsulfonyl group, a mono- or di-alkylamino group, an acylamino group,a carboxyl group, an alkoxycarbonyl group, an alkynylcarbonyl group, analkyl group, a cycloalkyl group, an aryl group, an aromatic heterocyclicgroup, etc.

These substituents may substitute on the aliphatic hydrocarbon group inchemically acceptable range. The number of the substituent is usually 1to 5 and preferably 1 to 3. When the number of substituent is more thantwo, the substituents may be the same or different from each other.

Examples of the halogen atom include fluorine, chlorine, bromine,iodine.

Examples of the alkoxy group include, for example, a C₁₋₁₀alkoxy groupsuch as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, pentyloxy, hexyloxy, etc.

Examples of the acyloxy group include, for example, formyloxy, aC₁₋₁₀alkyl-carbonyloxy (for example, acetoxy, propionyloxy, etc.), etc.Examples of the alkylthio group include, for example, a C₁₋₁₀alkylthiogroup such as methylthio, ethylthio, propylthio, isopropylthio, etc.Examples of the alkylsulfonyl group include, for example, aC₁₋₁₀alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl,propylsulfonyl, etc. Examples of the acyl amino group include, forexample, formylamino, diformylamino, a mono- ordi-C₁₋₁₀alkyl-carbonylamino (for example, acetylamino, propionylamino,butyrylamino, diacetylamino, etc.), etc. Examples of the alkoxycarbonylgroup include, for example, a C₁₋₁₀alkoxycarbonyl group such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, etc. Examples of the alkylcarbonyl group include, forexample, a C₁₋₁₀alkylcarbonyl group such as acetyl, propionyl, butyryl,valeryl, etc. Examples of the alkynylcarbonyl group include for example,a C₃₋₁₀alkynylcarbonyl group, such as acetylenylcarbonyl,1-propinylcarbonyl, 2-propinylcarbonyl, etc.

Examples of the cycloalkyl group include, for example, a C₃₋₁₀cycloalkylgroup such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.Examples of the aryl group include, for example, a C₆₋₁₄aryl group suchas phenyl, 1-naphthyl, 2-naphthyl, etc. Examples of the aromaticheterocyclic group include, for example, a mono- to tri-cyclic aromaticheterocyclic group containing one or two kind of hetero atoms andpreferably 1 to 4 hetero atoms selected from the group consisting ofnitrogen, oxygen and sulfur. Examples of the embodiment include, forexample, thienyl, pyridyl, furyl, pyrazinyl, pyrimidinyl, imidazolyl,pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridazinyl,tetrazolyl, quinolyl, indolyl, isoindolyl, etc. Examples of the alkylgroup include, for example, a C₁₋₁₀alkyl group such as methyl, ethyl,propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, etc.

Examples of the substituent which substitutes on the hydrocarbon groupmentioned above also include the following substituents, the number ofthe substituent is 1 to 5, preferably 1 to 3. Examples of thesubstituent include, for example, a halogen atom (for example, fluorine,chlorine, bromine, etc.), a hydroxy group, C₁₋₆alkoxy group (forexample, methoxy, ethoxy, propoxy, isopropoxy, etc.), etc.

Examples of the monocyclic aromatic heterocyclic group in the definitionof “monocyclic aromatic heterocyclic group which may be substituted”shown by R¹ include, for example, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, pyrazinyl, 2-pyrimidinyl,3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl,1-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl,4-isothiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,3-pyridazinyl, etc. Among them, 2-pyridyl, 3-pyridyl, 4-pyridyl,1-imidazolyl, 4-imidazolyl, etc., are preferable.

The substituent of “monocyclic aromatic heterocyclic group which may besubstituted” in the definition R¹ may substitute at the substitutableposition of the monocyclic aromatic heterocyclic group. The number ofthe substituent is 1 to 3. Examples of the substituent include an alkylgroup which may be substituted by 1 to 5 halogen atoms (e.g. fluorine,chlorine, bromine, iodine) (e.g. such a C₁₋₄alkyl as methyl, ethyl,propyl, etc., such a C₁₋₄alkyl substituted by halogen as2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, etc.), a C₁₋₃alkylgroup such as methyl, ethyl, propyl, isopropyl, etc., a C₁₋₃alkoxy groupsuch as methoxy, ethoxy, propoxy, isopropoxy, etc., a halogen atom suchas a chlorine atom, a fluorine atom, etc., a hydroxy group, an aminogroup, a nitro group, etc.

The preferable Examples of R¹ include a hydrogen atom, a lower(C₁₋₄)alkyl group which may be substituted, a lower(C₁₋₄) alkenyl group, acyclic(C₃₋₆) alkyl group, a phenyl group which may be substituted and apyridyl group which may be substituted each of which is mentioned above.Among them, a hydrogen atom, a lower(C₁₋₄) alkenyl group, a cyclic(C₃₋₆)alkyl group, a phenyl group, a pyridyl group and a lower(C₁₋₄) alkylgroup which may be substituted with halogen(s) are the most preferable.

The saturated hydrocarbon group which may be substituted and themonocyclic aromatic heterocyclic group which may be substitutedrepresented by R¹¹ have the same meaning as the hydrocarbon group whichmay be substituted and the monocyclic aromatic heterocyclic group whichmay be substituted, mentioned in the definition of R¹ and included inthe definition of R¹¹. The preferable examples of R¹¹ is the preferableexamples mentioned in the definition of R¹ and included in thedefinition of R¹¹.

The saturated hydrocarbon group which may be substituted and themonocyclic aromatic heterocyclic group which may be substitutedrepresented by R¹² have the same meaning as the those mentioned in thedefinition of R¹.

Examples of the lower alkyl group shown by R² include a straight chainor cyclic C₁₋₆alkyl group (e.g. methyl, ethyl, propyl, isopropyl,cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,cyclopentyl, hexyl, etc.) which may be substituted. The C₁₋₆alkyl groupmay be substituted by 1 to 5 substituents at any position. Examples ofthe substituent include, for example, a halogen (e.g. fluorine,chlorine, bromine, etc.), a C₁₋₄alkoxy group (e.g. methoxy, ethoxy,propoxy, etc.), etc.

Preferable examples of R² include a hydrogen atom and a non-substitutedlower(C₁₋₆) alkyl group among the lower alkyl group mentioned above, anda hydrogen atom is the most preferable.

The lower alkyl group which may be substituted represented by R²¹ hasthe same meaning as that mentioned in the definition of R².

The preferable examples of R²¹ is the preferable examples mentioned inthe definition of R² and included in the definition of R²¹.

Examples of the hydroxy group which may be substituted shown by R³, R⁴,R⁵, R⁶, R⁷, R⁸, R⁹ include an unsubstituted hydroxy group, a loweralkoxy (e.g. a C₁₋₄alkoxy group such as methoxy, ethoxy, propoxy, etc.),a lower alkanoyloxy (e.g. a C₁₋₄alkanoyloxy such as acetyloxy,propionyloxy, etc.), a carbamoyloxy which may be substituted (e.g.unsubstituted carbamoyloxy, methylcarbamoyloxy, ethylcarbamoyloxy,dimethylcarbamoyloxy, diethylcarbamoyloxy, methylethylcarbamoyloxy,etc., a carbamoyloxy substituted by 1 or 2 C₁₋₄alkyl group), etc.

Examples of the thiol group which may be substituted shown by R³, R⁴,R⁵, R⁶, R⁷, R⁸, R⁹ include unsubstituted thiol group, a lower alkylthio(e.g. a C₁₋₄alkylthio group such as methylthio, ethylthio, propylthio,etc.), a lower alkanoylthio (e.g. a C₁₋₄alkanoylthio such as acetylthio,propionylthio, etc.), etc.

Examples of the amino group which may be substituted shown by R³, R⁴,R⁵, R⁶, R⁷, R⁸, R⁹ include an unsubstituted amino group, a loweralkylamino (e.g. a C₁₋₄alkyl amino group such as methylamino,ethylamino, propylamino, etc.), a di-lower alkylamino (e.g. adi-C₁₋₄alkylamino such as dimethylamino, diethylamino, etc.), aC₁₋₄alkanoylamino (e.g. acetamide, propionamide, etc.), etc.

Examples of the acyl group represented by R³, R⁴, R⁵, R⁶, R⁷, R⁸ or R⁹include, for example, an alkanoyl group (e.g. formyl, a C₁₋₆alkanoylsuch as acetyl, propionyl, etc.), an alkylsulfonyl group (e.g.C₁₋₄alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, etc.), acarbamoyl group (mono- or di-C₁₋₁₀alkyl carbamoyl group such asmethylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl,etc., a mono- di-C₆₋₁₄ arylcarbamoyl group such as phenylcarbamoyl,diphenylcarbamoyl, etc., a mono- di-C₇₋₁₆aralkyl carbamoyl group such asbenzylcarbamoyl, dibenzylcarbamoyl, etc.), a sulfamoyl group which maybe substituted (a mono- or di-C₁₋₁₀alkylsulfamoyl group such asmethylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl,etc., a mono- or di-C₆₋₁₄ arylsulfamoyl group such as phenylsulfamoyl,diphenylsulfamoyl, etc., a mono- or di-C₇₋₁₆aralkyl sulfamoyl group suchas benzylsulfamoyl, dibenzylsulfamoyl, etc.), etc.

Examples of the halogen shown by R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ includefluorine, chlorine, bromine, iodine.

Examples of the hydrocarbon group which may be substituted shown by R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ include the same one as the hydrocarbon groupwhich may be substituted shown by R¹. Among them, a lower alkyl groupwhich may be substituted is preferable. Examples of the embodimentinclude a straight or cyclic C₁₋₆alkyl group (e.g. methyl, ethyl,propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, cyclopentyl, hexyl, etc.) which may be substituted. TheC₁₋₆alkyl group may be substituted by 1 to 5 substituents at anyposition. Examples of the substituent include, for example, a halogen(e.g. fluorine, chlorine, bromine, etc.), a C₁₋₄alkoxy group (e.g.methoxy, ethoxy, propoxy, etc.), a hydroxy group, etc. Examples of thelower alkoxy group which may be substituted include methoxy, ethoxy,propoxy, etc. The lower alkoxy group may be substituted by 1 to 5substituents at any position. Examples of the substituent include, forexample, a halogen (e.g. fluorine, chlorine, bromine, etc.), C₁₋₄alkoxygroup (e.g. methoxy, ethoxy, propoxy, etc.), etc. Preferable example ofR³, R⁴, R⁵, R⁶, R⁷, R⁸ or R⁹ include, for example, a hydrogen atom, ahydrocarbon group which may be substituted, a hydroxy group which may besubstituted, an amino group which may be substituted, a C₁₋₆acyl groupor a halogen atom each of which is mentioned above, and among them, ahydrogen atom, a hydrocarbon group which may be substituted, a hydroxygroup which may be substituted, an acyl group and a halogen atom aremore preferable.

As R⁷, a hydroxy group which may be substituted and a lower alkyl groupare preferable, and (1) a hydroxyl group which may be substituted with alower alkanoyl group, a lower alkanoyloxy-lower alkyl group, a loweralkyl group, a lower alkoxy-lower alkyl group, a lower alkyl grouphaving 1 to 4 fluorine atoms or a benzyl group, (2) a halogen atoms, (3)a lower alkyl group which may be substituted with a hydroxyl group, (4)a lower alkynyl group, (5) a lower alkanoyl group,(6) an amino groupwhich may be substituted with a lower alkanoyl group, a loweralkylaminocarbonyl group or a lower alkylsulfonyl group, or (7) a loweralkylthio group is more preferable. Among them, a lower alkyl group, alower alkoxy group and a lower alkanoylamino group are more preferableand a methoxy group is the most preferable.

As R⁸, hydrogen atom, a lower alkyl group and a lower alkoxy arepreferable and hydrogen atom and a lower alkoxy are more preferable. AsR⁶, (1) a hydrogen atom, (2) halogen atom, (3) a lower alkoxy group and(4) a lower alkyl group which may be substituted with a hydroxyl groupare preferable, and a hydrogen atom and a lower alkyl group are morepreferable.

It is preferable that one to three groups selected from the groupconsisting of R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are independently a loweralkyl group which may be substituted, a hydroxyl group which may besubstituted, an amino group which may be substituted, an acyl group or ahalogen atom.

It is more preferable that one to three groups selected from the groupconsisting of R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are independently a loweralkyl group which may be substituted, a hydroxyl group which may besubstituted or a C₁₋₆ acyl group.

It is preferable that one of R⁶, R⁷ and R⁸ is a lower alkyl group or alower alkoxy group, and each of R³, R⁴, R⁵ and R⁹ is a hydrogen atom

Among Compound (I), a compound wherein R¹¹ is a C₁₋₆alkyl group and R²¹is a hydrogen atom is preferable, and a compound wherein R¹¹ is anisopropyl group and R²¹ is a hydrogen atom is more preferable.

The preferable examples of the compound shown by the formula (I)include, for example, the compound of the formula:

(wherein each of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ has the meaningsshown above). Preferable example of the embodiments include, forexample,1-(1H-imidazol-4-yl-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol,1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol,1-(6-methoxy-5-methylnaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol,N-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}acetamide,1-(6-ethylnaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol andsalts thereof or prodrugs thereof.

The compound of the formula (I) may be a salt. Examples of the saltinclude a salt of inorganic acid (for example, a hydrochloric acid salt,a sulfuric acid salt, a hydrobromic acid salt, a phosphoric acid salt,etc.), a salt of an organic acid (for example, an acetic acid salt, atrifluoroacetic acid salt, a succinic acid salt, a maleic acid salt, afumalic acid salt, a propionic acid salt, a citric acid salt, a tartaricacid salt, a lactic acid salt, an oxalic acid salt, a methane sulfonicacid salt, a p-toluenesulfonic acid salt, etc.),etc., a salt with a base(for example, salt with an alkali metal such as a potassium salt, asodium salt, a lithium salt, etc., an alkaline earth metal salt such asa calcium salt, a magnesium salt, etc., an ammonium salt, a salt with anorganic base such as a trimethylamine salt, a triethyl amine salt,tert-butyldimethylamine salt, a dibenzylmethylamine salt, abenzyldimethylamine salt, a N,N-dimethylaniline salt, a pyridine salt, aquinoline salt, etc.).

The compound shown by (I) or a salt thereof may be a hydrate.Hereinafter these are referred to as Compound (I).

The pro-drug of Compound (I) means a compound which is converted tocompound (I) having steroid C_(17,20)-lyase inhibitory activity byenzymes, gastric acid, etc. in vivo.

Examples of the pro-drug of a compound (I) include a compound wherein anamino group of Compound (I) is substituted with acyl, alkyl, phosphoricacid, etc. (e.g. a compound wherein an amino group of Compound (I) issubstituted with eicosanoyl, alanyl, pentylaminocarbonyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl,pyrrolidylmethyl, pivaloyloxymethyl, tert-butyl, etc.); a compoundwherein an hydroxy group of Compound (I) is substituted with acyl,alkyl, phosphoric acid, boric acid, etc. (e.g. a compound wherein anhydroxy group of Compound (I) is substituted with acetyl, palmitoyl,propanoyl, pivaloyl, succinyl, fumaryl, alanyl,dimethylaminomethylcarbonyl, etc.); a compound wherein a carboxyl groupof Compound (I) is modified with ester, amide, etc. (e.g. a compoundwherein a carboxyl group of Compound (I) is modified with ethyl ester,phenyl ester, carboxymethyl ester, dimethylaminomethyl ester,pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidyl ester,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester,cyclohexyloxycarbonylethyl ester, methyl amide, etc.); etc. Thesepro-drug can be produced by per se known method.

The pro-drug of Compound (I) may be a compound which is converted intoCompound (I) under the physiological conditions as described in“Pharmaceutical Research and Development”, Vol. 7 (Drug Design), pages163–198 published in 1990 by Hirokawa Publishing Co. (Tokyo, Japan).

The compound (I) or a pro-drug thereof may be in the form of anypharmaceutically acceptable salts thereof. Examples of said saltsinclude a salt with inorganic bases (e.g., alkaline metals such assodium, potassium, etc.; alkaline earth metals such as calcium,magnesium, etc.; transition metal such as zinc, iron, copper, etc.;etc.); organic bases (e.g., organic amines such as trimethylamine,triethylamine, pyridine, picoline, ethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, N,N′-dibenzylethylenediamine, etc.;basic amino acids such as arginine, lysine, ornithine, etc.; etc.);etc., when said compound (I) has an acidic group such as a carboxylgroup, etc.; and a salt with inorganic acids or organic acids (e.g.,hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonicacid, bicarbonic acid, formic acid, acetic acid, propionic acid,trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleicacid, citric acid, succinic acid, malic acid, methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, etc.); acidic amino acidssuch as aspartic acid, glutamic acid, etc.; etc., when said compound (I)has a basic group such as an amino group, etc.

Also, Compound (I) may be hydrated.

Compound (I) may have one or more asymmetric carbons in the molecule.The compound of the present invention may have R-configuration orS-configuration as to the asymmetric carbons.

The “lower” in “a lower alkyl group”, “a lower alkoxy group”, etc.,throughout the present specification means a straight, branched orcyclic ones having 1 to 6 carbon otherwise mentioned.

In the present application, the compounds of the formulas (I′), (Ia),(Ib) and (Ic) are included in the compounds of the formula (I), and thecompounds of the formula (II′) are included in the compounds of theformula (II). Among the compound shown by the formulas (Ia), (Ib), (Ic),(II), (II′), (III), (IVa), (IVb), (IVc1), (IVc2), (IVd), (IVe1), (IVe2),(IVf), (Vb), (Vd), (VIa), (VIb), (VIc), (VId), (VIe) (VIf), (VIg),(VIIa), (VIIb) and (VIIc), compounds having a basic group or an acidicgroup can form a salt with acid or a salt with base, respectively.Examples of the salts include the salts of the compound (I) mentionedabove. Hereinafter the compound of the formula (Number of formula) andits salt are referred to as Compound (Number of formula). For example,both a compound of formula (IVa) and a salt thereof are referred to asCompound (IVa).

Compound (I) can be produced, for example, by the following processsteps.

The starting compound and an intermediate can be used as free form or asalt thereof like Compound (I). The reaction mixture as it is or afterisolation by a known method can be used for the following reaction.

[wherein X is a halogen atom, L is a leaving group (e.g. a halogen atom,an alkyl or aryl sulfonyloxy group, etc.), R²² is a lower alkyl groupwhich may be substituted, A¹¹ is a nitrogen-containing heterocyclicgroup which may be protected or/and substituted, and each of the othersymbols has the same meaning as defined above]

Examples of the nitrogen-containing heterocyclic group which may besubstituted in the definition of “nitrogen-containing heterocyclic groupwhich may be protected or/and substituted shown by A¹¹ include the sameas that mentioned above, and the protecting group is the same as thatmentioned below.

Examples of the metal shown by M include lithium or magnesium, etc.Examples of the salt of metal shown by M include, for example, a metalhalide such as magnesium chloride, magnesium bromide, etc.

The compound (IVa) is allowed to react with alkyl lithium or magnesiummetal, etc., to give an organometal compound (IVb). The compound (IVb)is allowed to react with an aldehyde (IVe1) or (IVe2) to give a compound(IVc1) or (IVc2), respectively. Examples of the alkyl lithium usedinclude a C₁₋₄alkyl lithium such as n-butyl lithium, s-butyl lithium,etc. The alkyl lithium is used in an amount of 1 to 3 moles, preferably1 to 1.5 moles per one mole of the starting material (IVa). The reactiontemperature in case of the reaction with alkyl lithium is in the rangeof −100° C. to 0° C., preferably −80° C. to −20° C. The temperature incase of the reaction with magnesium metal is in the range of −20° C. to100° C., preferably 10° C. to 50° C. The reaction time is about 5 min to20 h. The reaction is usually carried out in the presence of an organicsolvent which does not affect to the reaction. Examples of the organicsolvent which does not affect to the reaction include, for example, anether such as diethyl ether, dioxane, tetrahydrofuran (THF), etc., asaturated hydrocarbon such as hexane, pentane, etc., a halogenatedhydrocarbon such as dichloromethane, chloroform, etc., an aromatichydrocarbon such as benzene, toluene, etc. These solvent may be usedsolely or in combination of two or more in an appropriate ratio. Thealdehyde compound (IVe1) or (IVe2) is used in 0.5 to 10 equivalents,preferably 0.5 to 1.5 equivalents to Compound (IVb).

Compound (IVc1) or (IVc2) is allowed to alkylation to give a Compound(IVd) or (Ia), respectively. Examples of the alkylating agents (IVf)used include an alkyl halide (e.g. methyl iodide, ethyl bromide,isopropyl bromide, etc.), an ester of an alkyl or an aryl sulfonic acid(e.g. methyl methanesulfonate, ethyl p-toluenesulfonate, etc.), etc. Thealkylating agent can be used in an amount of 1 to 10 equivalents,preferably 1 to 2 equivalents to Compound (IVc1) or Compound (IVc2). Thereaction is usually carried out in a basic condition. Examples of thebase used include sodium hydride, potassium carbonate, sodium methylate,etc. The reaction is usually carried out in an inert solvent. Examplesof the solvent include, for example, dimethylformamide, an ether such astetrahydrofuran, etc., a halogenated hydrocarbon such asdichloromethane, etc. The reaction time is usually 30 min to 24 h,preferably 30 min to 10 h though it varies depend on the activity andamount of the alkylating agent and kind of the base. The reactiontemperature is usually −20° C. to 150° C.

By a similar manner to a known method, Compound (IVd) is allowed tode-protecting reaction which removes the protecting group of A¹¹ to giveCompound (Ia). For example, Compound (IVd) wherein A¹¹ has trityl group,that is, the nitrogen-containing heterocyclic group which may besubstituted is protected by trityl group, can be treated with acidiccondition or allowed to hydrogenolysis to remove the trityl group.Examples of the acid include an organic acid such as formic acid, aceticacid, etc., an inorganic acid such as hydrochloric acid, etc. Thereaction can be carried out in an inert solvent such as an alcohol, anether (e.g. tetrahydrofuran, etc.), etc. The reaction temperature isusually 0° C. to 100° C.

(wherein each symbol has the same meaning as defined above)

Compound (IVc2) is allowed to usual oxidation reaction to give Compound(Vb). The reaction is carried out by using manganese dioxide, chromicacid, etc., as an oxidizing agent in an inert solvent such asdichloromethane, chloroform, THF, etc. The reaction time is usually 30min to 48 h, preferably 30 min to 10 h. The reaction temperature isusually 0° C. to 100° C., preferably 20° C. to 70° C.

Compound (Vb) can be converted to Compound (II) by removing theprotecting group By a similar manner to a known method. The eliminationof the protecting group is carried out by a similar manner to theproduction of Compound (Ia) from Compound (IVd). Compound (II) isreacted with an organometal reagent (III) (an alkyl lithium reagent suchas methyl lithium, etc., a Grignard reagent such as ethyl magnesiumbromide, isopropyl magnesium chloride, etc.) to give Compound (Ib). Thereaction can be carried out by a per se known manner or, for example, amanner shown in Shin-jikkenkagaku-koza Vol. 14, p512 (Maruzen Co. Japan)or a manner similar to these methods. The organometal reagent (III) isused in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalentsto the ketone (II). The reaction temperature is −100° C. to 50° C.,preferably −80° C. to 20° C. The reaction time is 5 min to 20 h. Thereaction is usually carried out in the presence of an organic solventwhich does not affect to the reaction. Examples of the organic solventwhich does not affect to the reaction include, for example, an ethersuch as diethyl ether, dioxane, tetrahydrofuran, etc., a saturatedhydrocarbon such as hexane, pentane, etc., a halogenated hydrocarbonsuch as dichloromethane, chloroform, etc., an aromatic hydrocarbon suchas benzene, toluene, etc. These solvent may be used solely or incombination of two or more in an appropriate ratio.

Compound (Ib) can also be produced by reacting Compound (Vb) withCompound (III) to give Compound (Vd), followed by subjecting Compound(Vd) to deprotection reaction.

[wherein R′ is a group shown by the formula: OR″ or by the formula:NR″R′″ (wherein each of R″ and R′″ is a lower alkyl group or a loweralkyloxy group. NR″R′″ may be a cyclic amine residue such as amorpholino group, a pyrrolidino group, etc.). A¹² is anitrogen-containing heterocyclic group which may be protected or/andsubstituted, and each of the other symbols has the same meaning asdefined above]

Examples of the nitrogen-containing heterocyclic group which may beprotected or/and substituted among the nitrogen-containing heterocyclicgroup which may be protected or/and substituted shown by A¹², includethe same as that mentioned about A¹¹, and that having no protectinggroup is the same as that mentioned about A.

Compound (VIa) is reacted with (VIb) by known Friedel-Crafts reaction,the manner shown in Shin-jikkenkagaku-koza Vol. 14, p511 (Maruzen Co.Japan) or a manner similar to those manner, to give the carbonylcompound (VIc). Compound (VIc) can also be produced by reacting Compound(IVb) with Compound (VIe). The reaction is carried out in an inertsolvent such as THF, dichloromethane, etc. Compound (IVb) is used in anamount of 0.2 to 2 equivalents, preferably 0.2 to 1.5 equivalents toCompound (VIe). The reaction temperature is −80° C. to 50° C.,preferably −80° C. to 20° C.

Compound (Vd) can be produced by subjecting Compound (VIc) to alkylationreaction by using Compound (VId). The reaction can be carried out by asimilar manner to the production of Compound (Ib) from Compound (II).

Compound (Vd) can also be produced by reacting an organometal reagent(IVb) with a ketone (VIf) By a similar manner to the production ofCompound (Ib) from Compound (II). Compound (Vd) wherein thenitrogen-containing heterocyclic group is protected can be converted toCompound (Ib) by removing the protecting group by a similar manner tothe production of Compound (Ia).

[wherein each symbol has the same meaning as defined above.]

Compound (Ic) can be produced by subjecting Compound (Vd) to alkylationreaction by using Compound (IVf) to give Compound (VIg), followed byremoving the protecting group. The alkylation reaction is carried out bya similar manner to the production of Compound (IVd) from Compound(IVc2). The elimination of the protecting group is carried out by asimilar manner to the production of Compound (Ia) from Compound (IVd).

(wherein each symbol has the same meaning as defined above.)

Compound (VIa) is reacted with (VIIa) by a known Friedel-Craftsreaction, the manner shown in Shin-jikkenkagaku-koza Vol. 14, p511(Maruzen co. Japan) or a manner similar to those manner, to give acarbonyl compound (VIIc). Compound (VIIc) can also be produced byreacting Compound (IVb) with Compound (VIIb). The reaction is carriedout in an inert solvent such as THF, dichloromethane, etc. Compound(IVb) is used in an amount of 0.2 to 2 equivalents, preferably 0.2 to1.5 equivalents to Compound (VIIb). The reaction temperature is usually−80° C. to 50° C., preferably −80° C. to 20° C.

When the desired compound is obtained in free form, the compound may beconverted to a salt by a conventional manner. When the desired compoundis obtained in a salt, the compound can be converted to free form by aconventional manner. Compound (I) thus obtained can be isolated from thereaction mixture and purified by a known procedure such as phasetransfer, concentration, solvent extraction, fractional distillation,crystallization, recrystallization, chromatography, etc. In the abovereactions, an amino group, a carboxyl group, a hydroxy group, each ofwhich is not involved in the reaction, in the compound or a salt thereofwhich is to be reacted may be protected. The protection with aprotecting group and deprotection can be carried out by a known manner.Examples of the protecting group of an amino group include, for example,formyl, a C₁₋₆alkylcarbonyl (for example, acetyl, propionyl, etc.), aphenyl carbonyl, a C₁₋₆alkyl-oxycarbonyl (for example, methoxycarbonyl,ethoxycarbonyl, etc.), phenyloxycarbonyl, a C₇₋₁₀aralkyloxy-carbonyl(for example, a phenyl-C₁₋₄alkyloxy-carbonyl such as benzyloxycarbonyl,etc.), trityl, phthaloyl or N,N-dimethylaminomethylene, etc., each ofwhich may be substituted. Examples of the substituent include a halogenatom (for example, fluorine, chlorine, bromine, iodine, etc.), formyl, aC₁₋₆alkyl-carbonyl (for example, acetyl, propionyl, valeryl, etc.),nitro, etc. The number of substituent is about 1 to 3.

Examples of the protecting group of a carboxyl group include, forexample, a C₁₋₆alkyl (for example, methyl, ethyl, propyl, isopropyl,butyl, tert-butyl, etc.), phenyl, trityl or silyl, etc., each of whichmay be substituted. Examples of the substituent include, a halogen atom(for example, fluorine, chlorine, bromine, iodine, etc.), formyl, aC₁₋₆alkyl-carbonyl (for example, acetyl, propionyl, valeryl, etc.),nitro, etc. The number of substituent is about 1 to 3.

Examples of the protecting group of a hydroxy group include, forexample, a C₁₋₆alkyl (for example, methyl, ethyl, propyl, isopropyl,butyl, tert-butyl, etc.), phenyl, a C₇₋₁₀aralkyl (for example, aphenyl-C₁₋₄alkyl such as benzyl, etc.), formyl, a C₁₋₆alkyl-carbonyl(for example, acetyl, propionyl, etc.), phenyloxycarbonyl, benzoyl, a(C₇₋₁₀aralkyloxy)carbonyl (for example, a phenyl-C₁₋₄alkyloxy-carbonylsuch as benzyloxycarbonyl, etc.), pyranyl, furanyl or silyl, etc., eachof which may be substituted. Examples of the substituent include ahalogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), aC₁₋₆alkyl (for example, methyl, ethyl, propyl, etc.), phenyl, aC₇₋₁₀aralkyl (for example, a phenyl-C₁₋₄alkyl such as benzyl, etc.),nitro, etc. The number of substituent is about 1 to 4.

The deprotection reaction is carried out by a known manner or a similarmanner thereof. Examples of the deprotection reaction include a mannertreating with, for example, acid, base, reduction, ultraviolet ray,hydrazine, phenyl hydrazine, sodium N-methyldithiocarbamate,tetrabutylammonium fluoride, palladium acetate, etc.

When Compound (I) is diastereomer, conformer, etc., Compound (I) can beisolated and purified by a isolation procedure or purification procedurementioned above, if desirable. When Compound (I) is a racemate, (+)-formand (−)-form of Compound (I) can be isolated by a usual opticalresolution procedure. When Compound (I) has a basic group, it can beconverted to a salt with acid by a known manner.

Compound (I) has superior effect for medicine, and especially has asuperior inhibitory activity of steroid C_(17,20)-lyase. Compound (I) isless toxic and has little adverse side effect. Compound (I) is usefulfor the preventing and treating a mammal (for example, humans, bovines,horses, dogs, cats, monkeys, mice, rats, etc., especially humans)suffering from various disease such as (1) primary cancer of malignanttumor (for example, prostate cancer, breast cancer, uterine cancer,ovarian cancer, etc.), and its metastasis and recurrence, (2) varioussymptoms accompanied with these cancer (for example, pain, cachexia,etc.), (3) prostatic hypertrophy, virilism, hirsutism, male patternalopecia, precocious puberty, endometriosis, uterus myoma, adenomyosisof uterus, mastopathy, polycystic ovary syndrome, etc.

While Compound (I) has a superior effect when used solely, the effectcan be promoted by using the compound (I) in combination with othermedicaments and remedies. Examples of the medicament and remedy,include, for example, sex hormones, alkylating agents, antimetabolites,antitumor antibiotics, plant alkaloids, immunotherapies, etc., but notlimited to.

Examples of the hormone like agent include, for example, Fosfestrol,Diethylstilbestrol, chlorotrianisene, Medroxyprogesterone acetate,Megestrol acetate, Chlormadinone acetate, Cyproterone acetate, Danazol,Allylestrenol, Gestrinone, Mepartricin, Raloxifene, Ormeloxifene,Levormeloxifene, antiestrogens (for example, Tamoxifen, Toremifene,etc.), the contraceptive pill, Mepitiostane, Testolactone,Aminoglutethimide, LH-RHagonist (for example, Goserelinacetate,Buserelin, Leuprorelin, etc.), LH-RH antagonist (for example, Ganirelix,Cetrorelix, Abarelix, etc.), Droloxifene, Epitiostanol, Ethinylestradiolsulfonate, aromatase inhibitors(for example, Fadrozole, Anastrozole,Letrozole, Exemestane, Vorozole, Formestane, etc.), anti-androgens (forexample, Flutamide, Bicalutamide, Nilutamide, etc.), 5α-reductaseinhibitors (for example, Finasteride, Epristeride, etc.), adrenocorticalhormones (for example, Dexamethasone, Prednisolone, Betamethasone,Triamcinclone, etc.), inhibitors of androgen-synthesis (for example,Abiraterone, etc.), Retinoid and suppressing agents of Retinoidmetabolism (for example, Liarozole, etc.), etc.

Examples of the alkylating agents include, for example, Nitrogenmustard, Nitrogen mustard N-oxide hydrochloride, Chlorambucil,Cyclophosphamide, Ifosfamide, Thiotepa, Carboquone, Improsulphantosilate, Busulfan, Nimustine, Mitobronitol, Melphalan, Dacarbazine,Ranimustine, Estramustine phosphate sodium, Triethylenemelamine,Carmustine, Lomustine, Streptozocin, Pipobroman, Ethoglucid,Carboplatin, Cisplatin, Miboplatin, Nedaplatin, Oxaliplatin,Altretamine, Ambamustine, Dibrospidium chloride, Fotemustine,Prednimustine, Pumitepa, Ribomustin, Temozolomide, Treosulfan,Trofosfamide, Zinostatin stimalamer, Carboquone, Adozelesin,Cystemustine, Bizelesin, etc.

Examples of the antimetabolites include, for example, Mercaptopurine,6-Mercaptopurine riboside, Thiomosine, Methotrexate, Enocitabine,Cytarabine, Cytarabine ocfosfate, Ancitabine hydrochloride, 5-FUanalogues (for example, Fluorouracil, Tegafur, UFT, Doxifluridine,Carmofur, Galocitabine, Emitefur, etc.), Aminopterin, Leucovorincalcium, Tabloid, Butocin, Calcium folinate, Calcium levofolinate,Cladribine, Emitefur, Fludarabine, Gemcitabine, Hydroxycarbamide,Pentostatin, Piritrexim, Idoxuridine, Mitoguazone, Tiazofurin,Ambamustine, etc.

Example of antitumor antibiotics include, for example, Actinomycin D,Actinomycin C, Mitomycin C, Chromomycin A3, Bleomycin hydrochloride,Bleomycin sulfate, Peplomycin sulfate, Daunorubicin hydrochloride,Doxorubicin hydrochloride, Aclarubicin hydrochloride, Pirarubicinhydrochloride, Epirubicin hydrochloride, Neocarzinostatin, Mithramycin,Sarkomycin, Carzinophilin, Mitotane, Zorubicin hydrochloride,Mitoxantrone hydrochloride, Idarubicin hydrochloride, etc.

Examples of the plant alkaloid include, for example, Etoposide,Etoposide Phosphate, Vinblastine sulfate, Vincristine sulfate, Vindesinesulfate, Teniposide, Paclitaxel, Vinorelbine, etc.

Examples of the immunotherapy (BRM) include, for example, Picibanil,Krestin, Sizofiran, Lentinan, Ubenimex, Interferons, Interleukins,Macrophage-colony stimulating factor, granules stimulating factor ofspheroid colony, Erythropoietin, Lymphotoxin, BCG vaccine,Corynebacterium parvum, Levamisole, Polysaccharide-K, Procodazol, etc.

Others: L-asparaginase, Aceglatone, Procarbazine hydrochloride,Protoporphyrin, Hematoporphyrin, topoisomerase Iinhibitors (for example,Irinotecan, Topotecan, etc.), topoisomerase Iiinhibitors (for example,Sobuzoxane, etc.), differentiation promoter (for example, Retinoid,Vitamin D, etc.), inhibitor of proliferation factor (for example,Suramin, etc.), Angiogenesis inhibitors, α-broker (for example,Tamsulosin hydrochloride, etc.), Tyrosin kinase inhibitors, etc.

Examples of the other remedy include operation, thermotherapy,radiotherapy, etc. Therapies other than chemotherapies, such as anoperation including orchidectomy, thermotherapy, radiotherapy, etc., canbe conducted together with the administration of Compound (I).

Examples of the pharmaceutically acceptable carrier include variousorganic or inorganic carriers which are used as a pharmaceuticalingredients. Exipients, lubricants, binders, disintegrators, thickenerscan be used for solid preparations; solvents, dispersants, solbilizingagents, suspending agents, isotonic agents, buffer agents, soothingagents, etc., can be used for liquid preparations. If necessary,additives such as preservatives, antioxidants, coloring agents,sweetening agents, etc., can be used. Examples of the preferableexipient include, for example, lactose, saccharoseu, D-mannitol, starch,crystalline cellulose, light anhydrous silicic acid, etc. Examples ofthe preferable lubricant include, for example, magnesium stearate,calcium stearate, talc, colloidal silica, etc. Examples of thepreferable binder include, for example, crystalline cellulose,saccharose, D-mannitol, dextrin, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinyl pyrolidone, etc. Examples of thepreferable disintegrator include, for example, starch,carboxymethylcellulose, carboxymethylcellulose calcium, crosscarmelosesodium, carboxymethyl starch sodium, etc. Examples of the preferablethickener include, for example, natural rubbers, cellulose derivatives,acrylic acid polymers, etc. Examples of the preferable solvent include,for example, water for injection, alcohol, propyleneglycol, Macrogol,sesame oil, corn oil, etc. Examples of the preferable dispersantinclude, for example, Tween 80, HCO 60, polyethylene glycol,carboxymethylcellulose, sodium alginate, etc. Examples of the preferablesolbilizing agent include, for example, polyethylene glycol,propyleneglycol, D-mannitol, benzoic acid benzyl, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate, etc. Examples of the preferable suspending agent include, forexample, surfactants such as stearyl triethanolamine, sodiumlaurylsulfate, lauryl aminopropionic acid, lecithin, benzalkoniumchloride, benzethonium chloride, glycerin monostearate, etc.; forexample, hydrophilic polymer such as polyvinylalcohol, polyvinylpyrolidone, sodium carboxymethyl cellulose, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,etc. Examples of the preferable isotonic agent include, for example,sodium chloride, glycerin, D-mannitol, etc. Examples of the preferablebuffer agent include, for example, buffer solution such as phosphoricacid salt, acetic acid salt, carbonate, citric acid salt, etc. Examplesof the preferable soothing agent include, for example, benzyl alcohol,etc. Examples of the preferable preservative include, for example,paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethylalcohol,dehydroacetic acid, sorbic acid, etc. Examples of the preferableantioxidant include, for example, sulfurous acid salt, ascorbic acid,etc.

The pharmaceutical preparation of the present invention can bemanufactured by a usual manner. The ratio of Compound (I) contained in apharmaceutical preparation is usually 0.1 to 100% (w/w). Examples of theembodiment of the pharmaceutical preparation are as follows:

(1) Tablets, Powder, Granules, Capsules:

These preparations can be prepared by adding, for example, exipients,disintegrators, binders or lubricants, etc., to Compound (I), bycompressive molding the mixture and, if necessary, by coating formasking of taste, enteric or sustained release.

(2) Injections:

These preparations can be prepared by dissolving Compound (I) in aqueousinjection together with, for example, dispersants, preservatives,isotonic agents, etc., or by dissolving, dispersing or emulsifyingCompound (I) in a vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil, etc., or propyleneglycol, etc., to give an oilyinjection.

(3) Suppositories:

These preparations can be produced by preparing a liquid compositioncontaining Compound (I), which may be oily, aqueous solid like oraqueous semisolid like. Examples of the oily base used for thecomposition include, for example, triglycerin ester of long-chain fattyacid (for example, cacao butter, witepsols, etc.), middle-chain fattyacid (for example, migriols, etc.), vegetable oils (for example, sesameoil, soybean oil, cotton seed oil, etc.), etc. Examples of the aqueousgel base include, for example, natural rubber, cellulose derivative,vinyl polymer, acrylic acid polymer, etc.

The content of Compound (I) in these preparation is usually 0.01 to 50%,though it varies depending upon the kind of pharmaceutical preparation.

The rate of the compound of the present invention in the abovepharmaceutical preparation, varies depending upon the compound used,kind of animal to which the compound is administered, number ofadministration times, etc. The daily dose of the compound of the presentinvention, for example, for adult humans suffering from solid tumors (apatient suffering from, for example, prostate cancer), is usually about0.001 to about 500 mg/kg-weight, preferably about 0.1 to about 40mg/kg-weight, more preferably about 0.5 to about 20 mg/kg-weight. WhenCompound (I) is non-orally administered or when it is administered incombination with an other anti-cancer agent, Compound (I) isadministered in a less amount mentioned above. A dose of Compound (I)actually administered are decided by a doctor by taking kind ofcompound, type of pharmaceutical preparation, age of the patient, bodyweight, sex, degree of disease, administration route, administrationterm and its interval, etc., into consideration, and the dose may bechanged by a doctor.

The pharmaceutical preparation can be administered orally orparenterally. Examples of the parenteral administration route includeintravenous, intramuscular, subcutaneous, intranasal, intradermal,instillation, intracerebral, intrarectal, intravaginal andintraperitoneal, etc.

The above mentioned administration term and administration intervalvaries depending upon the various conditions and decided by a doctor. Asthe administration, there may be mentioned divided administration, dailyadministration, intermittent administration, high dose administrationtherapy in short term, repeat administration, etc. It is preferable toadminister the compound, for example, once to some times a day(especially two or three times a day). It is possible to administer thecompound once to some times a day when oral administration. It is alsopossible to the compound as a sustained release preparation. It is alsopossible to the compound by intravenous drip infusion over a long time

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is hereinafter described in more detail by meansof the following Examples, pharmaceutical preparations and ExperimentalExamples, but these are merely described as examples and they are notintended to limit the present invention. The meanings of the followingabbreviated symbols are as follows.

s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, dt:double triplet, m: multiplet, br: broad, J: coupling constant, roomtemperature: 0˜30° C., DMF: dimethylformamide, THF: tetrahydrofuran.

EXAMPLE 1 Production of1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol

(i) Production of(6-methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)methanol

2-Bromo-6-methoxynaphthalene (30 g) was dissolved in THF (400 ml), andthe solution was cooled at −78° C. To the solution was added dropwise asolution of n-butyllithium in hexane (1.6 M; 99 ml), and the mixture wasstirred at −78° C. for 30 min. To the mixture was slowly added dropwisea solution of 4-formyl-1-trityl-1H-imidazole (38.9 g) in THF (300 ml),and the mixture was stirred at −78° C. for 30 min. The reaction mixturewas poured into a 3% aqueous solution of citric acid (600 ml) andpartitioned. The organic layer was separated, and the aqueous layer wasextracted with ethyl acetate. The organic layers were combined, washedwith saturated aqueous solution of sodium chloride, dried andconcentrated. The residue was washed with ethyl acetate to give thetitled compound as a colorless solid (35.0 g).

¹H-NMR (CDCl₃) δ: 3.90 (3H, s), 5.89 (1H, s), 6.60 (1H, d, J=1.4 Hz),7.08–7.15 (8H, m), 7.26–7.34 (9H, m), 7.42–7.47 (2H, m), 7.63–7.69 (2H,m), 7.78 (1H, s) IR (KBr): 3166, 1603, 1478, 1451, 1260, 1171, 1128,754, 702 cm⁻¹.

(ii) Production of(6-methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone

(6-methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)methanol (18.0 g)was dissolved in chloroform (300 ml), and to the solution was addedmanganese dioxide (56 g). The mixture was heated for 1 h under reflux.The reaction mixture was filtered and concentrated. Crystallization ofthe residue from ether gave the titled compound (17.0 g) as a colorlesssolid.

¹H-NMR (CDCl₃) δ: 3.94 (3H, s), 7.15–7.23 (8H, m) 7.34–7.40 (9H, m),7.58 (1H, d, J=1.3 Hz), 7.78 (1H, d, J=1.3 Hz), 7.78 (1H, d, J=8.6 Hz),7.86 (1H, d, J=9.6 Hz), 8.26 (1H, dd, J=8.6, 1.6 Hz), 8.95 (1H, s) IR(KBr): 1620, 1520, 1493, 1480, 1445, 1265, 1196, 1179, 909, 872, 747,733, 702 cm⁻¹.

(iii) Production of (1H-imidazol-4-yl)-(6-methoxynaphthalen-2-yl)ketone

(6-Methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl) ketone (15.0 g)was dissolved in THF (80 ml). To the solution was added 90% formic acid(20 ml), and the mixture was stirred at 50° C. for 2 h. After removal ofthe solvents by evaporation, 1N-hydrochloric acid (60 ml) was added andthe precipitate was filtered off. The filtrate was washed with ether,and neutralized with potassium carbonate. The resulting precipitate wascollected by filtration, dried under reduced pressure to give the titledcompound (7.54 g) as a colorless solid.

¹H-NMR (CDCl₃+CD₃OD) δ: 3.97 (3H, s), 7.26–7.21 (2H, m), 7.78 (1H, s),7.82–7.91 (3H, m), 7.99 (1H, dd, J=8.5, 1.7 Hz), 8.49 (1H, s) IR (KBr):1636, 1624, 1481, 1346, 1264, 1169, 1024, 1005 cm⁻¹.

(iv) Production of1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol

(1H-Imidazol-4-yl)-(6-methoxynaphthalen-2-yl)ketone (6.50 g) wasdissolved in THF(120 ml), and the solution was cooled to −10° C. To thesolution was slowly added dropwise a solution of isopropyl magnesiumchloride in THF (2.0 M; 38.7 ml), and the mixture was stirred at −10° C.for 30 min. To the reaction mixture was added saturated aqueous solutionof ammonium chloride and water. The mixture was extracted with ethylacetate. The extract was washed with saturated aqueous solution ofsodium chloride, dried and concentrated. The residue was purified bysilica gel column chromatography (eluent,chloroform:methanol=20:1→10:1). Recrystallization from ethyl acetategave the titled compound (5.04 g) as a colorless crystalline powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.81 (3H, d, J=6.8 Hz), 1.00 (3H, d, J=6.8 Hz),2.64–2.78 (1H, m), 3.91 (3H, s), 7.00 (1H, d, J=1.0 Hz), 7.09–7.15 (2H,m), 7.51–7.56 (2H, m), 7.65–7.75 (2H, m), 7.91 (1H, d, J=1.4 Hz) IR(KBr): 3140, 2984, 2957, 1464, 1222, 1028, 856, 806, 652 cm⁻¹

EXAMPLE 2 Production of1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)ethanol

(i) Production of1-(6-methoxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)ethanol

(6-Methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl) ketone (2.50 g)was dissolved in THF(20 ml), and the solution was cooled to 0° C. To thesolution was slowly added dropwise a solution of methylmagnesium bromidein ether (3.0M, 3.4 ml), and the mixture was stirred for 20 min at 0° C.To the reaction mixture was added saturated aqueous solution of ammoniumchloride and water. The mixture was extracted with ethyl acetate. Theextract was washed with saturated aqueous solution of sodium chloride,dried and concentrated to give the titled compound (2.51 g) as acolorless powder.

¹H-NMR (CDCl₃) δ: 1.85 (3H, s), 3.62 (1H, br-s), 3.90 (3H, s), 6.77 (1H,d, J=1.4 Hz), 7.09 (1H, s), 7.131–7.21 (7H, m), 7.30–7.36 (9H, m), 7.41(1H, d, J=1.4 Hz), 7.45 (1H, dd, J=8.7 Hz, 1.8 Hz), 7.62–7.69 (2H, m),7.80 (1H, d, J=1.6 Hz)

IR (KBr): 3150, 1605, 1493, 1445, 1264, 1177, 1165, 909, 747, 733, 702cm⁻¹.

(ii) Production of1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)ethanol

1-(6-Methoxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)ethanol (2.20g) was dissolved in 90% formic acid (15 ml), and the solution wasstirred at room temperature for 15 h. To the solution was added 1N-hydrochloric acid, and precipitate was filtered off. The filtrate wasneutralized with potassium carbonate, and extracted with ethyl acetate.The extract was washed with saturated aqueous solution of sodiumchloride, dried and concentrated. The residue was purified by silica gelcolumn chromatography (eluent, ethylacetate:methanol=20:1→chloroform:methanol=10:1) to give the titledcompound (1.05 g) as a colorless solid.

¹H-NMR (CDCl₃+CD₃OD) δ: 1.94 (3H, s), 3.92 (3H, s), 6.88 (1H, s),7.11–7.16 (2H, m), 7.46 (1H, dd, J=8.5, 1.9 Hz), 7.53 (1H, d, J=1.0 Hz),7.67 (1H, d, J=3.4 Hz), 7.72 (1H, d, J=5.2 Hz), 7.82 (1H, d, J=1.2 Hz)

IR (KBr): 3160, 1607, 1485, 1453, 1264, 1171, 1115, 893, 847 cm⁻¹

EXAMPLE 3 Production of1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-2,2,2-trifluoroethanol

(6-Methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone (1.0 g) wasdissolved in THF(10 ml) and to the solution was addedtrifluoromethyltrimethylsilane (1.40 g). The reaction mixture was cooledto 0° C., and tetrabutylammonium fluoride (0.4 ml) was added. Themixture was stirred at room temperature for 2 h. To the mixture wereadded 1 N-hydrochloric acid (10 ml) and isopropanol (5 ml), and themixture was stirred at room temperature for 24 h. The reaction mixturewas neutralized, and extracted with ethyl acetate. The extract waswashed with saturated aqueous solution of sodium chloride, dried andconcentrated. The residue was purified by silica gel columnchromatography (eluent, chloroform:methanol=20:1→10:1).Recrystallization from ethyl acetate gave the titled compound (0.40 g)as a colorless powder.

¹H-NMR(CDCl₃+CD₃OD) δ: d 3.92 (3H, s), 7.10–7.18 (3H, m) 7.59 (1H, d,J=1.0 Hz), 7.63 (1H, s), 7.71 (1H, d, J=3.6 Hz), 7.76 (1H, d, J=4.2 Hz),8.02 (1H, s)

IR (KBr): 3000, 1487, 1395, 1265, 1165, 899, 889, 858 cm⁻¹.

EXAMPLE 4 Production ofcyclopropyl-(6-methoxynaphthalen-2-yl)-(1H-imidazol-4-yl)methanolfumarate

(1H-Imidazol-4-yl)-(6-methoxynaphthalen-2-yl)ketone (0.97 g) wasdissolved in THF(20 ml), and the solution was cooled to 0° C. To thesolution was slowly added dropwise a solution of cyclopropylmagnesiumbromide in THF (1.7 M; 8 ml), and the mixture was stirred for 30 min at0° C. To the reaction mixture was added saturated aqueous solution ofammonium chloride. The mixture was diluted with water, and neutralizedwith 1 N-hydrochloric acid. The dilution was extracted with ethylacetate, washed with saturated aqueous solution of sodium chloride,dried and concentrated. The residue was purified by silica gel columnchromatography (eluent, chloroform:methanol=20:1). To the obtainedcompound (0.53 g) was added fumaric acid (0.21 g). Recrystallizationfrom methanol gave the titled compound (0.50 g) as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 0.32–0.62 (4H, m), 1.62–1.76 (1H, m), 2.49–2.52 (1H,m), 6.61 (2H, s), 3.86 (3H, s), 7.04 (1H, d, J=1.2 Hz), 7.12 (1H, dd,J=8.8, 2.4 Hz), 7.25 (1H, d, J=2.4 Hz), 7.52 (1H, dd, J=8.7, 1.7 Hz),7.65–7.79 (3H, m), 7.89 (1H, s)

IR (KBr): 1609, 1265, 1227, 1179, 1163, 1063, 851 cm⁻¹

EXAMPLE 5

Production of2,2-dimethyl-1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-1-propanolfumarate

In a similar manner to that described in Example 4, the reaction andpurification were carried out by using(1H-imidazol-4-yl)-(6-methoxynaphthalen-2-yl)ketone (0.80 g) and asolution of tert-butylmagnesium chloride in THF (2.0 M, 4.8 ml), wherebythe titled compound (0.47 g) was obtained as a pale yellow solid.

¹H-NMR (CD₃OD) δ: 1.06 (9H, s), 3.89 (3H, s), 6.71 (2H, s), 7.62 (1H,dd, J=8.8, 2.0 Hz), 7.69–7.70 (2H, m), 7.80 (1H, d, J=1.2 Hz), 7.93 (1H,s), 8.50 (1H, s)

IR (KBr) 1535, 1391, 1271, 1215, 1167, 899, 851 cm⁻¹.

EXAMPLE 6 Production of(1H-imidazol-4-yl)-(6-methoxynaphthalen-2-yl)-(pyridin-3-yl)methanol

(i) Production of(6-methoxynaphthalen-2-yl)-(pyridin-3-yl)-(1-trityl-1H-imidazol-4-yl)methanol

3-Bromopyridine (0.92 ml) was dissolved in ether (20 ml), and thesolution was cooled at −78° C. To the solution was slowly added dropwisea solution of n-butyllithium in hexane (1.6 M; 5.9 ml), the mixture wasstirred for 20 min at −78° C. To the reaction mixture was slowly added asolution of (6-methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone(1.0 g) in THF (8 ml), and the mixture was stirred for 30 min at −78° C.To the reaction mixture was added water, and mixture was diluted with 2%citric acid (50 ml). The dilution was extracted with ethyl acetate,washed with saturated aqueous solution of sodium chloride, dried andconcentrated. The residue was recrystallized from a mixed solution ofethyl acetate and diethyl ether to give the titled compound (0.98 g) asa pale yellow powder.

¹H-NMR (CDCl₃) δ: 3.90 (3H, s), 6.40 (1H, d, J=1.4 Hz), 7.09–7.23 (9H,m), 7.27–7.41 (10H, m), 7.50 (1H, d, J=1.6 Hz), 7.57–7.65 (3H, m),7.70–7.76 (1H, m), 8.47 (1H, dd, J=4.8, 1.6 Hz), 8.54 (1H, d, J=2.2 Hz)

IR (KBr): 3216, 1609, 1485, 1443, 1389, 1269, 1171, 1067, 1028, 878,849, 748, 702 cm⁻¹.

(ii) Production of(1H-imidazol-4-yl)-(6-methoxynaphthalen-2-yl)-(pyridin-3-yl)methanol

(6-Methoxynaphthalen-2-yl)-(pyridin-3-yl)-(1-trityl-1H-imidazol-4-yl)methanol(0.80 g) was dissolved in 90% solution of formic acid (3 ml), and thesolution was stirred at 50° C. for 30 min. To the solution was added 1N-hydrochloric acid, and precipitate was filtered off. The filtrate waswashed with ether, and neutralized with potassium carbonate. Thefiltrate was extracted with chloroform and concentrated. The residue waspurified by silica gel column chromatography (eluent,chloroform:methanol=5:1). Recrystallization from THF gave the titledcompound (0.36 g) as a colorless powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 3.92 (3H, s), 6.44 (1H, s), 7.12–7.16 (2H, m),7.25–7.29 (1H, m), 7.43 (1H, dd, J=8.5, 1.7 Hz), 7.64–7.71 (4H, m), 7.80(1H, dd, J=8.0, 1.6 Hz), 8.44 (1H, dd, J=3.4, 1.2 Hz), 8.54 (1H, d,J=2.4 Hz)

IR (KBr) 3058, 2840, 1422, 1265, 1167, 1152, 1034, 891, 851, 806 cm⁻¹

EXAMPLE 7 Production of(1H-imidazol-4-yl)-(6-methoxynaphthalen-2-yl)-(pyridin-4-yl)methanol

(i) Production of(6-methoxynaphthalen-2-yl)-(pyridin-4-yl)-(1-trityl-1H-imidazol-4-yl)methanol

In a similar manner to that described in Example 6-(i), the reaction of4-bromopyridine (0.92 ml) with(6-methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone (1.0 g) wascarried out to give the titled compound (0.88 g) as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 3.85 (3H, s), 6.49 (1H, s), 6.83 (1H, d, J=1.4 Hz),7.11–7.15 (7H, m), 7.25 (1H, d, J=1.4 Hz), 7.37–7.43 (13H, m), 7.67–7.74(3H, m), 8.44–8.47 (2H, m)

IR (KBr): 1605, 1483, 1447, 1265, 1223, 1169, 1130, 1063, 1036, 762,748, 702 cm⁻¹.

(ii) Production of(1H-imidazol-4-yl)-(6-methoxynaphthalen-2-yl)-(pyridin-4-yl)methanol

In a similar manner to that described in Example 6-(ii), a reaction andpurification were carried out by using(6-methoxynaphthalen-2-yl)-(pyridin-4-yl)-(1-trityl-1H-imidazol-4-yl)methanol(0.70 g) to give the titled compound (0.36 g) as a colorless solid.

¹H-NMR (CDCl₃+CD₃OD) δ: 3.92 (3H, s), 6.50 (1H, d, J=1.4 Hz), 7.10–7.16(2H, m), 7.39–7.44 (3H, m), 7.64–7.72 (4H, m), 8.47 (2H, dd, J=4.6, 1.6Hz)

IR (KBr): 3067, 2840, 1601, 1414, 1265, 1167, 893, 866, 853 cm⁻¹

EXAMPLE 8 Production of1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-1-phenylmethanol

(i) Production of1-(6-methoxynaphthalen-2-yl)-1-phenyl-1-(1-trityl-1H-imidazol-4-yl)methanol

In a similar manner to that described in Example 6-(i), the reaction ofbromo benzene (0.85 ml) with(6-methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone (1.0 g) wascarried out. The reaction mixture was purified by silica gel columnchromatography (eluent, hexane:ethyl acetate=3:1→2:1) to give the titledcompound (0.98 g) as a pale yellow powder.

¹H-NMR (CDCl₃) δ: 3.89 (3H, s), 6.40 (1H, d, J=1.4 Hz), 7.07–7.33 (22H,m), 7.41 (1H, dd, J=8.6, 1.6 Hz), 7.47 (1H, d, J=1.4 Hz), 7.58–7.63 (3H,m).

IR (KBr): 3167, 1742, 1609, 1485, 1447, 1265, 1165, 1132, 1030, 889,849, 756, 700 cm⁻¹.

(ii) Production of1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-1-phenylmethanol

In a similar manner to that described in Example 6-(ii), a reaction andpurification were carried out by using1-(6-methoxynaphthalen-2-yl)-1-phenyl-1-(1-trityl-1H-imidazol-4-yl)methanol(0.80 g) to give the titled compound (0.31 g) as a colorless solid.

¹H-NMR (CDCl₃+CD₃OD) δ: 3.91, (3H, s) 6.41 (1H, s), 7.08–7.13 (2H, m),7.25–7.39 (5H, m),7.44 (1H, dd, J=8.7, 1.7 Hz), 7.59 (1H, d, J=1.2 Hz),7.63–7.64 (2H, m), 7.68 (1H, d, J=2.6 Hz)

IR (KBr): 3362, 2838, 1607, 1389, 1264, 1221, 1167, 1034, 862, 756 cm⁻¹.

EXAMPLE 9 Production of1-(6-methoxynaphthalen-2-yl)-2-methyl-1-(pyridin-4-yl)-1-propanol

(i) Production of (6-methoxynaphthalen-2-yl)(pyridin-4-yl)methanol

In a similar manner to that described in Example 1-(i), the reaction of2-bromo-6-methoxynaphthalene (15 g) with isonicotinic aldehyde (8.14 g)was carried out to give the titled compound (7.8 g) as a pale yellowsolid.

¹H-NMR (CDCl₃) δ: 1.80 (1H, br s), 3.92 (3H, s), 5.93 (1H, s), 7.11 (1H,d, J=2.4 Hz), 7.16 (1H, dd, J=8.8, 2.6 Hz), 7.33–7.37 (3H, m), 7.70 (1H,s), 7.74 (2H, s), 8.51 (1H, d, J=1.4 Hz), 8.53 (1H, d, J=1.6 Hz)

IR (KBr) 3133, 1634, 1603, 1507, 1483, 1416, 1391, 1265, 1219, 1167,1030, 849, 818 cm⁻¹.

(ii) Production of (6-methoxynaphthalen-2-yl)-(pyridin-4-yl)-ketone

In a similar manner to that described in Example 1-(ii), a reaction andpurification were carried out by using(6-methoxynaphthalen-2-yl)-(pyridin-4-yl)methanol (2.0 g) to give thetitled compound (1.76 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 3.97 (3H, s), 7.20 (1H, s), 7.81 (1H, d, J=4.2 Hz),7.24–7.27 (1H, m), 7.61 (1H, d, J=1.6 Hz), 7.64 (1H, d, J=1.6 Hz), 7.85(1H, d, J=4.6 Hz), 7.93–7.98 (1H, m), 8.18 (1H, d, J=1.8 Hz), 8.83 (1H,d, J=1.2 Hz), 8.85 (1H, d, J=1.2 Hz)

IR (KBr): 1651, 1622, 1483, 1466, 1406, 1287, 1265, 1219, 1024, 862,828, 720 cm⁻¹

(iii) Production of1-(6-methoxynaphthalen-2-yl)-2-methyl-1-(pyridin-4-yl)-1-propanol

In a similar manner to that described in Example 1-(iv), the reaction of(6-methoxynaphthalen-2-yl)-(pyridin-4-yl)ketone (0.6 g) was carried outto give the titled compound (0.34 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.90 (3H, d, J=6.8 Hz), 0.96 (3H, d, J=6.6 Hz), 2.30(1H, br s), 3.05–2.91 (1H, m), 3.90 (3H, s), 7.08–7.17 (2H, m),7.44–7.54 (3H, m), 7.66–7.75 (2H, m), 7.93 (1H, d, J=1.6 Hz), 8.49 (2H,d, J=6.2 Hz)

IR (KBr): 3102, 1601, 1412, 1265, 1221, 1165, 1062, 853, 820, 810, 683cm⁻¹

EXAMPLE 10 Production of1-(6-methoxynaphthalen-2-yl)-2-methyl-1-(pyridin-3-yl)-1-propanol

(i) Production of (6-methoxynaphthalen-2-yl)-(pyridin-3-yl)methanol

In a similar manner to that described in Example 1-(i), the reaction of2-bromo-6-methoxynaphthalene (15.0 g) with nicotinic aldehyde (8.14 g)was carried out to give the titled compound (11.47 g) as a pale yellowsolid.

¹H-NMR (CDCl₃) δ: 0.91 (3H, d, J=2.4 Hz), 0.95(3H,dd,J=2.4 Hz), 1.75(1H, br-s), 3.92 (3H, s), 6.02 (1H, s), 7.12–7.30 (3H, m), 7.38 (1H, dd,J=8.5, 1.7 Hz), 7.70–7.79 (4H, m), 8.50 (1H, dd, J=4.9, 1.5 Hz), 8.67(1H, d, J=2.0 Hz)

IR (KBr) 3183, 1609, 1591, 1451, 1426, 1271, 1167, 1057, 1032, 909, 839,818, 720 cm^(−1.)

(ii) Production of (6-methoxynaphthalen-2-yl)-(pyridin-3-yl) ketone

In a similar manner to that described in Example 1-(ii), a reaction andpurification were carried out by using(6-methoxynaphthalen-2-yl)-(pyridin-3-yl)methanol (3.0 g) to give thetitled compound (2.77 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 3.97 (3H, s), 7.21–7.26 (2H, m), 7.46–7.52 (1H, m),7.81–7.93 (2H, m), 7.95 (1H, dd, J=8.5, 1.1 Hz), 8.14–8.21 (2H, m), 8.84(1H, dd, J=4.8, 1.2 Hz), 9.05 (1H, d, J=2.0 Hz)

IR (KBr): 1653, 1622, 1584, 1480, 1296, 1281, 1215, 1146, 1026, 895, 737cm⁻¹

(iii) Production of1-(6-methoxynaphthalen-2-yl)-2-methyl-1-(pyridin-3-yl)-1-propanol

In a similar manner to that described in Example 1-(iv), a reaction wascarried out by using(6-methoxynaphthalen-2-yl)-(pyridin-3-yl)ketone-(0.65 g) to give thetitled compound (0.34 g) as a pale yellow solid.

¹H-NMR (CDCl₃) δ: 0.91 (3H, d, J=2.4 Hz), 0.95 (3H, d, J=2.4 Hz),2.90–3.04 (1H, m), 3.90 (3H, s), 7.08–7.22 (3H, m), 7.49 (1H, dd, J=8.5,1.9 Hz), 7.65–7.75 (2H, m), 7.82–7.88 (1H, m), 7.93 (1H, d, J=1.8 Hz),8.40 (1H, d, J=4.0 Hz), 8.77 (1H, s)

IR (KBr): 3227, 2971, 1481, 1466, 1424, 1391, 1265, 1167, 1026, 878,864, 802 cm−1

EXAMPLE 11 Production of1-(5-fluoro-6-methoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

In a similar manner to that described in Example 1-(iv), a reaction wascarried out by using(5-fluoro-6-methoxynaphthalen-2-yl)-(1H-imidazol-4-yl)ketone (0.32 g) togive the titled compound (0.18 g) as a pale yellow solid.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.80 (3H, d, J=6.8 Hz), 1.01 (3H, d, J=6.6 Hz),2.63–2.76 (1H, m), 4.00 (3H, s), 6.70 (1H, d, J=1.2 Hz), 7.22–7.30 (1H,m), 7.51–7.65 (3H, m), 7.93–8.02 (2H, m)

IR (KBr): 1495, 1383, 1362, 1281, 1098, 1053, 1019, 980, 797 cm⁻¹

EXAMPLE 12 Production of1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-1-propanol

In a similar manner to that described in Example 1-(iv), the reaction of(1H-imidazol-4-yl)-(6-methoxynaphthalen-2-yl) ketone (0.60 g) with asolution of ethyl magnesium bromide in ether (3.0 M, 2.4 ml) was carriedout to give the titled compound (0.28 g) as a colorless solid.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.87 (3H, t, J=7.3 Hz), 2.19–2.41 (2H, m), 3.92(3H, s), 6.91 (1H, d, J=1.2 Hz), 7.11–7.16 (2H, m), 7.42 (1H, dd, J=8.8,1.2 Hz), 7.54 (1H, d, J=1.2 Hz), 7.66–7.75 (2H, m), 7.86 (1H, d, J=1.4Hz)

IR (KBr): 3160, 2971, 1607, 1483, 1265, 1223, 1169, 1032 cm⁻¹

EXAMPLE 13 Production of1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-3-methyl-1-butanol

In a similar manner to that described in Example 1-(iv), the reaction of(1H-imidazol-4-yl)-(6-methoxynaphthalen-2-yl)ketone (0.60 g) with asolution of isobutylmagnesium bromide in THF (1.0 M, 2.4 ml) was carriedout to give the titled compound (0.14 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.72 (3H, d, J=6.8 Hz), 0.94 (3H, d, J=6.8 Hz),1.63–1.82 (1H, m), 2.20 (2H, d, J=5.8 Hz), 3.90 (3H, s), 6.82 (1H, s),7.10–7.14 (2H, m), 7.38 (1H, s), 7.42 (1H, dd, J=8.4, 1.8 Hz), 7.63–7.72(2H, m), 7.93 (1H, d, J=1.4 Hz)

IR (KBr): 2953, 1607, 1505, 1483, 1466, 1265, 1389, 1219, 1169, 1032,853 cm⁻¹

EXAMPLE 14 Production of1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-1-butanol

In a similar manner to that described in Example 1-(iv), the reaction of(1H-imidazol-4-yl)-6-methoxynaphthalen-2-yl ketone (0.60 g) andn-propylmagnesium bromide in THF (1.0 M, 2.4 ml) to give the titledcompound (0.53 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.89 (3H, t, J=7.3 Hz), 1.10–1.30 (1H, m), 1.37–1.55(1H, m), 2.20–2.30 (2H, m), 3.91 (3H, s), 6.90 (1H, s), 7.10–7.15 (2H,m), 7.45 (1H, dd, J=8.6, 1.8 Hz), 7.50 (1H, s), 7.65–7.73 (2H, m), 7.91(1H, s)

IR (KBr): 2955, 1605, 1505, 1483, 1265, 1221, 1167, 1032, 850 cm⁻¹

EXAMPLE 15 Production of1-cyclopentyl-1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)methanol

In a similar manner to that described in Example 1-(iv), the reaction of(1H-imidazol-4-yl)-(6-methoxynaphthalen-2-yl) ketone (0.60 g) withcyclopentylmagnesium bromide in THF (1.0 M, 10 ml)was carried out togive the titled compound (0.80 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 1.34–1.72 (8H, m), 2.92–3.06 (1H, m), 3.90 (3H, s),7.02 (1H, s), 7.09–7.14 (2H, m), 7.51–7.56 (2H, m), 7.63–7.74 (2H, m),7.97 (1H, s)

IR (KBr): 2959, 1607, 1483, 1265, 1221, 1169, 1032, 851 cm⁻¹

EXAMPLE 16 Production of1-(6-acetoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

(i) Production of(6-benzyloxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)methanol

In a similar manner to that described in Example 1-(i), a reaction wascarried out by using 2-benzyloxy-6-bromonaphthalene (7 g) to give thetitled compound as a colorless powder (5.5 g).

¹H-NMR (CDCl₃) δ: 5.17(2H,s), 5.90(1H,s), 6.65(1H,s), 7.08–7.90(27H,m)

IR (KBr): 3061, 1633, 1604, 1483, 1446, 1390 cm⁻¹

(ii) Production of(6-benzyloxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone

In a similar manner to that described in Example 1-(ii), a reaction wascarried out by using(6-benzyloxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)methanol (4.18g) to give the titled compound (3.25 g) as a colorless powder.

¹H-NMR (CDCl₃) δ: 5.20(2H,s), 7.10–7.92(26H,m), 8.25(1H,dd,J=8.8, 1.0Hz)

IR (KBr): 3061, 1620, 1521, 1180 cm⁻¹

(iii) Production of1-(6-benzyloxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol

In a similar manner to that described in Example 1-(iv), a reaction wascarried out by using(6-benzyloxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone (4.3 g)to give the titled compound (2.6 g) as a colorless powder.

¹H-NMR (CDCl₃) δ: 0.74(3H,d,J=6.8 Hz), 0.94(3H, d, J=6.8 Hz), 2.42–2.62(1H,m), 3.67(1H,s), 5.17(2H,s), 6.80(1H, d, J=1.4 Hz), 7.05–7.75(26H,m),7.94(1H,s)

IR (KBr): 3061, 2968, 1631, 1603, 1493, 1444, 1386 cm⁻¹

(iv) Production of1-(6-hydroxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol

1-(6-Benzyloxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol(2.4 g) was dissolved in a mixed solution of THF and methanol (1:1, 160ml). To the solution was added 10% palladium carbon (0.8 g). The mixturewas stirred for 5 h under hydrogen atmosphere. The catalyst was filteredoff, and filtrate was concentrated. The residue was crystallized fromTHF-ethyl acetate to give the titled compound (1.20 g) as a colorlesspowder.

¹H-NMR (CDCl₃) δ: 0.74(3H,d,J=6.6 Hz), 0.95(3H,d,J=6.6 Hz), 2.45–2.65(1H,m), 6.80–7.86(23H,m)

IR (KBr): 3061, 2968, 1631, 1603, 1493, 1444, 1168 cm⁻¹

(v) Production of1-(6-acetoxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol

A mixture of1-(6-hydroxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol(1.0 g), pyridine (4 ml) and anhydrous acetic acid (4 ml) was stirred atroom temperature for 14 h. The reaction mixture was concentrated todryness, and the residue was dissolved in ethyl acetate and washed withwater and saturated aqueous solution of sodium chloride. The solutionwas dried and concentrated. The residue was crystallized from ethylacetate-diisopropyl ether to give the titled compound (0.6 g) as acolorless powder.

¹H-NMR (CDCl₃) δ: 0.72(3H,d,J=6.6 Hz), 0.96(3H,d,J=6.6 Hz), 2.42–2.62(1H,m), 6.80(1H, d, J=1.2 Hz), 7.0–7.82(21H,m), 8.02(1H,s)

(vi) Production of1-(6-acetoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

1-(6-Acetoxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol(0.25 g) was dissolved in acetic acid (20 ml). To the mixture was added10% palladium carbon (0.1 g). The mixture was stirred at 50° C. for 2 hunder hydrogen atmosphere. The catalyst was filtered off, and filtratewas concentrated. The residue was purified by silica gel chromatography(eluent; dichloromethane-methanol=10:1) to give the titled compound (0.1g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.78(3H,d,J=7 Hz), 1.00(3H,d,J=7 Hz), 2.35(3H,s),2.59–2.79(1H,m), 6.93(1H,s), 7.18(1H,dd,J=8.8, 2.6 Hz), 7.41(1H,s), 7.49(1H,d,J=2.6 Hz), 7.60(1H,dd,J=8.8, 1.8 Hz), 7.71(1H,d,J=8.4), 7.81(1H,d,J=8.8 Hz), 8.04(1H,s)

IR (KBr): 3130, 2968, 1759, 1604, 1369, 1205 cm⁻¹

EXAMPLE 17 Production of1-(6-hydroxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

1-(6-Benzyloxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol(0.9 g) was dissolved in acetic acid (20 ml), and to the solution wasadded 10% palladium carbon(0.25 g). The mixture was stirred at 50° C.for 2 h under hydrogen atmosphere. The catalyst was filtered off, andthe filtrate was concentrated. The residue was purified by silica gelchromatography (eluent dichloromethane-methanol=10:1). Crystallizationfrom methanol-ethyl acetate-diisopropyl ether gave the titled compound(0.30 g) as a colorless powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.81(3H,d,J=7 Hz), 1.00(3H,d,J=7 Hz), 2.03(1H,s), 2.60–2.80(1H,m), 6.95–7.15(3H,m), 7.40–7.72(4H,m), 7.86(1H,s)

EXAMPLE 18 Production of1-(1-acetoxymethyl-1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol

1-(1H-Imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol(100 mg) was dissolved in THF (6 ml), and to the solution were addedbromomethyl acetate(160 mg) and triethylamine (40 mg). The mixture wasstirred at room temperature for 2 h. The reaction mixture wasconcentrated, and the residue was purified by silica gel chromatography(eluent, dichloromethane-methanol=20:1) to give the titled compound (30mg) as a colorless solid.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.79(3H,d,J=7 Hz), 0.97(3H,d,J=7 Hz), 2.07(3H,s), 2.61–2.81(1H,m), 3.40(1H,br), 3.90(3H,s), 5,76(2H,s),7.00–7.17(3H,m), 7.55–7.78(4H,m), 8.02(1H,s)

EXAMPLE 19 Production of4-[1-methoxy-1-(6-methoxynaphthalen-2-yl)ethyl]-1H-imidazole

(i) Production of4-[1-methoxy-1-(6-methoxynaphthalen-2-yl)ethyl]-1-trityl-1H-imidazole

Sodium hydride (60% oil dispersion, 286 mg) was dispersed in THF (20ml), and to the dispersion was added1-(6-methoxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)ethanol (3.05g) under ice cooling. The mixture was stirred for 20 min, and methyliodide (0.41 ml) was added. The mixture was stirred for 50 min undercooling. The reaction was quenched by the addition of water, and thereaction mixture was extracted with ethyl acetate, saturated aqueoussolution of sodium chloride and concentrated. The residue wasrecrystallized from ether-hexane (1:1) to give the titled compound as apale yellow powder (2.95 g).

¹H-NMR (CDCl₃) δ: 1.94 (3H, s), 3.18(3H, s), 3.89 (3H, s), 6.77 (1H, d,J=1.4 Hz), 7.09–7.17 (8H, m), 7.30–7.33 (9H, m), 7.41–7.48 (2H, m),7.63–7.72 (2H, m), 7.82 (1H, d, J=1.6 Hz).

IR (KBr): 1603, 1483, 1445, 1264, 1188, 1148, 1111, 1026 cm⁻¹

(ii) Production of4-[1-methoxy-1-(6-methoxynaphthalen-2-yl)ethyl]-1H-imidazole

4-[1-Methoxy-1-(6-methoxynaphthalen-2-yl)ethyl]-1-trityl-1H-imidazole(1.5 g) and pyridine hydrochloride (500 mg) were dissolved in methanol(8 ml). The solution was stirred at 60° C. for 2 h. After cooling, 1N-hydrochloric acid was added to the solution, and precipitate wasfiltered off. The filtrate was washed with ether and neutralized withpotassium carbonate. The filtrate was extracted with ethyl acetate,washed with saturated aqueous solution of sodium chloride, dried andconcentrated. The residue was purified by silica gel columnchromatography (eluent, ethyl acetate:methanol=30:1) to give the titledcompound (0.33 g) as a colorless powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 1.93 (3H, s), 3.21 (3H, s), 3.92 (3H, s), 6.93(1H, d, J=1.2 Hz), 7.12–7.17 (2H, m), 7.43 (1H, dd, J=1.8, 8.6 Hz), 7.68(1H, d, J=4.2 Hz), 7.73 (1H, d, J=4.8 Hz), 7.79 (1H, d, J=1.8 Hz).

IR (KBr): 3002, 2957, 1607, 1483, 1460, 1273, 1208, 1103, 1026, 855 cm⁻¹

EXAMPLE 20 Production of1-(1H-imidazol-4-yl)-1-(naphthalen-2-yl)-2-methyl-1-propanol

(i)Production of (1H-imidazol-4-yl)-(naphthalen-2-yl)ketone

4-Bromo-1H-imidazole(1.95 g) was dissolved in THF (30 ml), and thesolution was cooled to −78° C. To the solution was added a solution oft-butyllithium in pentane (1.7 M; 20 ml). The mixture was stirred at 0°C. for 1.5 h. The mixture was again cooled to −78° C., and a solution of2-formylnaphthalene (3.32 g) in THF (20 ml) was added. After thetemperature was elevated from −78° C. to room temperature, the mixturewas stirred at room temperature for 16 h. To the mixture was added anaqueous solution of ammonium chloride, and the mixture was extractedwith ethyl acetate. The organic layer was dried and concentrated. Theresidue was purified by silica gel column chromatography (eluent,dichloromethane:methanol=10:1). Recrystallization fromdichloromethane-methanol gave the titled compound (1.00 g) as acolorless solid.

¹H-NMR (CDCl₃) δ: 7.53–7.70 (2H, m), 7.84–8.40 (6H, m), 8.53 (1H, s),10.82 (1H, brs).

IR (KBr): 2592, 1640, 1127, 779 cm⁻¹.

(ii) Production of1-(1H-imidazol-4-yl)-1-(naphthalen-2-yl)-2-methyl-1-propanol

In a similar manner to that described in Example 1-(iv), a reaction wascarried out by using (1H-imidazol-4-yl)-(naphthalen-2-yl)ketone (0.629g) to give 1-(1H-imidazol-4-yl)-1-(naphthalen-2-yl)-2-methyl-1-propanol(0.338 g).

¹H-NMR (CDCl₃) δ: 0.79 (3H, d, J=6.8 Hz), 1.00 (3H, d, J=6.8 Hz), 2.69(1H, m), 6.94 (1H, s), 7.34–7.48 (3H, m), 7.57 (1H, dd, J=1.8, 8.6 Hz),7.50–7.84 (3H, m), 8.02 (1H, s).

IR (KBr): 2969, 1470, 1128, 909, 816, 733 cm⁻¹.

EXAMPLE 21 Production of(−)-1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanoland(+)-1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol

1-(1H-Imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanolobtained in Example 1 was subjected to high performance liquidchromatography [column; CHIRALPAK AD (Produced by Daicel Chemical Co.Japan, 10 mm×250 mm), eluent; hexane-ethanol=7:3] to isolate opticalantipode. (−)-Enantiomer was obtained from the first eluent and(+)-enantiomer was obtained from the second eluent.

EXAMPLE 22 Production of4-[1-methoxy-1-(6-methoxynaphthalen-2-yl)-2-methylpropyl]-1H-imidazole

(i) Production of1-(6-methoxynaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

In a similar manner to that described in Example 1-(iv), a reaction wascarried out by using(6-methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone (4.0 g).Recrystallization from ether gave the titled compound (2.79 g) as acolorless powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.74 (3H, d, J=6.8 Hz), 0.94 (3H, d, J=6.6 Hz),1.90 (1H, br s), 2.46–2.59 (1H, m), 3.91 (3H, s), 6.80 (1H, d, J=1.4Hz), 7.09–7.17 (8H, m), 7.29–7.37 (m, 10H), 7.53 (1H, dd, J=1.7, 8.7Hz), 7.62–7.71 (2H, m), 7.93 (1H, d, J=1.2 Hz).

IR (KBr) 1605, 1483, 1445, 1264, 1223, 1167, 909, 747 cm⁻¹.

(ii) Production of4-[1-methoxy-1-(6-methoxynaphthalen-2-yl)-2-methylpropyl]-1-trityl-1H-imidazole

In a similar manner to that described in Example 19-(i), a reaction wascarried out by using1-(6-methoxynaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(2.8 g). The reaction mixture was purified by silica gel chromatography(hexane:ethyl acetate=2:1) to give the titled compound (2.68 g) as apale yellow powder.

¹H-NMR (CDCl₃) δ: 0.79 (3H, d, J=6.4 Hz), 0.82 (3H, d, J=6.6 Hz),2.90–3.03 (1H, m), 2.98 (3H, s), 3.90 (3H, s), 6.74 (1H, d, J=1.4 Hz),7.09–7.23 (8H, m), 7.30–7.35 (9H, m), 7.47 (1H, dd, J=1.8, 8.6 Hz), 7.56(1H, d, J=1.4 Hz), 7.62–7.67 (2H, m), 7.79 (1H, d, J=1.4 Hz).

IR (KBr): 2961, 1605, 1481, 1447, 1264, 1169, 1074, 747, 702 cm⁻¹

(iii) Production of4-[1-methoxy-1-(6-methoxynaphthalen-2-yl)-2-methylpropyl]-1H-imidazole

In a similar manner to that described in Example 19-(ii), a reaction wascarried out by using4-[1-methoxy-1-(6-methoxynaphthalen-2-yl)-2-methylpropyl]-1-trityl-1H-imidazole(2.0 g). Recrystallization from ethyl acetate gave the titled compound(0.90 g) as a colorless powder.

¹H-NMR (CDCl₃) δ: 0.84 (6H, d, J=6.6 Hz), 2.74–2.87 (1H, m), 2.97 (3H,s), 3.91 (3H, s), 7.08–7.16 (3H, m), 7.43 (1H, dd, J=1.8, 8.6 Hz), 7.60(1H, s), 7.66–7.74 (2H, m), 7.79 (1H, s).

IR (KBr): 3067, 2967, 1628, 1603, 1483, 1389, 1265, 1169, 1030, 1073,849, 837, 820 cm-1

EXAMPLE 23 Production of4-[Methoxy-(6-methoxynaphthalen-2-yl)methyl]-1H-imidazole

(i)Production of4-[Methoxy-(6-methoxynaphthalen-2-yl)methyl]-1-trityl-1H-imidazole

Sodium hydride (60% oil dispersion, 1.77 g) was added to a mixture ofTHF (200 ml) and DMF (100 ml). To the mixture was added(6-methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)methanol (20.0 g).The mixture was heated at 50° C. until the evolution of hydrogen ceased.The mixture was cooled to 0° C., and to the mixture was added methyliodide (2.6 ml). The mixture was stirred for 15 min. Water was added tothe reaction mixture to quench the reaction. THF was distilled off underreduced pressure. To the residue was added water, and the mixture wasextracted with ethyl acetate. The extract was washed with water andsaturated aqueous solution of sodium chloride, dried and concentrated.The residue was recrystallized from ethyl acetate-hexane to give thetitled compound (18.6 g) as a colorless powder.

¹H-NMR (CDCl₃) δ: 3.36 (3H, s), 3.90 (3H, s), 5.39 (1H, s), 6.74 (1H, d,J=0.6 Hz), 7.09–7.15 (8H, m), 7.25–7.32 (9H, m), 7.38 (1H, d, J=1.4 Hz),7.47 (1H, dd, J=1.7, 8.5 Hz), 7.67–7.73 (2H, m), 7.79 (1H, s).

IR (KBr): 1605, 1483, 1445, 1260, 1233, 1211, 1190, 1091 cm⁻¹

(ii) Production of4-[Methoxy-(6-methoxynaphthalen-2-yl)methyl]-1H-imidazole

In a similar manner to that described in Example 19-(ii), a reaction wascarried out by using4-[Methoxy-(6-methoxynaphthalen-2-yl)methyl]-1-trityl-1H-imidazole (5.0g). The crystals obtained was washed with water and ether and dried togive the titled compound (2.58 g) as a colorless powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 3.41 (3H, s), 3.93 (3H, s), 5.44 (1H, s), 6.74(1H, s), 7.13–7.17 (2H, m), 7.47 (1H, dd, J=1.5, 8.4 Hz), 7.57 (1H, s),7.72 (1H, s), 7.76 (1H, s), 7.80 (1H, s).

IR (KBr): 3085, 2996, 2826, 1605, 1485, 1460, 1235, 1177, 1086, 1076,1028, 900, 781 cm⁻¹

EXAMPLE 24 Production of4-[isopropoxy-(6-methoxynaphthalen-2-yl)methyl]-1H-imidazole

(i) Production of4-[isopropoxy-(6-methoxynaphthalen-2-yl)methyl]-1-trityl-1H-imidazole

(6-Methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)methanol (12.5 g)was dissolved in pyridine (100 ml), and to the mixture was added benzoylchloride (3.5 ml) under ice cooling. The mixture was stirred at roomtemperature for 3 h, and to the mixture was added saturated aqueoussolution of hydrogen bicarbonate (150 ml). The resulting crystals werewashed with water and ether to give a benzoate (15.3 g) as a colorlesssolid. The benzoate (1.6 g) was dissolved in a mixture of isopropanol(10 ml) and dioxane (10 ml), and the solution was stirred at 80° C. for4 h. The solution was diluted with a saturated aqueous solution ofhydrogen bicarbonate, extracted with dichloromethane, washed with asaturated aqueous solution of hydrogen bicarbonate and concentrated. Theresidue was recrystallized from THF-hexane to give the titled compound(1.1 g) as a colorless powder.

¹H-NMR (CDCl₃) δ: 1.18 (6H, d, J=6.2 Hz), 3.66–3.79 (1H, m), 3.90 (3H,s), 5.62 (1H, s), 6.74 (1H, d, J=1.4 Hz), 7.09–7.15 (8H, m), 7.26–7.32(9H, m), 7.39 (1H, d, J=1.6 Hz), 7.49 (1H, dd, J=1.7, 8.5 Hz), 7.66–7.72(2H, m), 7.75 (1H, s).

IR (KBr): 1607, 1483, 1445, 1264, 1165, 1125, 1034, 747, 700 cm⁻¹

(ii)Production of4-[isopropoxy-(6-methoxynaphthalen-2-yl)methyl]-1H-imidazole

In a similar manner to that described in Example 19-(ii), a reaction wascarried out by using4-[isopropoxy-(6-methoxynaphthalen-2-yl)methyl]-1-trityl-1H-imidazole(1.0 g) to give the titled compound (0.45 g) as a pale yellow powder.

¹H-NMR (CDCl₃) δ: 1.16 (3H, d, J=6.2 Hz), 1.21 (3H, d, J=6.0 Hz),3.65–3.77 (1H, m), 3.90 (3H, s), 5.65 (1H, s), 6.73 (1H, s), 7.10–7.15(2H, m), 7.44–7.49 (2H, m), 7.66 (1H, d, J=2.8 Hz), 7.70 (1H, s), 7.75(1H, s).

IR (KBr): 2970, 1609, 1483, 1265, 1169, 1123, 1034, 853 cm⁻¹

EXAMPLE 25 Production of1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-2-methyl-2-propen-1-ol

In a similar manner to that described in Example 1-(iv), the reaction of(1H-imidazol-4-yl)-(6-methoxynaphthalen-2-yl)ketone (0.80 g) with2-propen-2-ylmagnesium bromide in THF (1.0 M, 9.5 ml) was carried out togive the titled compound (0.76 g) as a colorless powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 1.80 (3H, s), 3.94 (3H, s), 4.83 (1H, s), 5.14(1H, s), 6.57 (1H, d, J=1.2 Hz), 7.11–7.19 (2H, m), 7.58 (1H, dd, J=2.0,8.6 Hz), 7.64 (1H, d, J=1.0, 8.6 Hz), 7.71 (1H, d, J=3.2 Hz), 7.76 (1H,d, J=3.2 Hz), 7.83 (1H, d, J=1.4 Hz).

IR (KBr): 3196, 2994, 2677, 1466, 1269, 1223, 1117, 1051, 1032, 856, 831cm⁻¹

EXAMPLE 26 Production of1-(5-chloro-6-methoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

(i) Production of(5-chloro-6-methoxynaphthalen-2-yl)-(1H-imidazol-4-yl)ketone

In a similar manner to that described in Example 20-(i),(5-chloro-6-methoxynaphthalen-2-yl)-(1H-imidazol-4-yl)ketone (0.784 g)was synthesized from 1-chloro-6-formyl-2-methoxynaphthalene (1.474 g).

¹H-NMR(DMSO-d₆) δ: 4.07 (3H, s), 7.66 (1H, d, J=9.2 Hz), 7.96 (2H, m),8.15–8.24 (3H, m), 8.92 (1H, s).

IR (KBr): 2573, 1632, 1441, 1348, 1279, 1069 cm⁻¹.

(ii) Production of1-(5-chloro-6-methoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

In a similar manner to that described in Example 1-(iv),1-(5-chloro-6-methoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol(0.117 g) was synthesized from(5-chloro-6-methoxynaphthalen-2-yl)-(1H-imidazol-4-yl)ketone (0.537 g).

¹H-NMR (CDCl₃) δ: 0.79 (3H, d, J=6.8 Hz), 1.00 (3H, d, J=6.8 Hz), 2.69(1H, m), 4.01 (3H, s), 6.98 (1H, d, J=1.1 Hz), 7.21–7.30 (1H, m), 7.48(1H, d, J=1.1 Hz), 7.66 (1H, dd, J=9.2, 1.6 Hz), 7.73 (1H, d, J=8.8 Hz),8.02 (1H, d, J=1.6 Hz), 8.12 (1H, d, J=9.2 Hz).

IR (KBr): 2969, 1601, 1275, 1071 cm⁻¹.

EXAMPLE 27 Production of1-[5-[1-(tert-butyldimethylsilyloxy)ethyl]-6-methoxynaphthalen-2-yl]-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

(i) Production of 1-acetyl-6-bromo-2-methoxynaphthalene.

2-Bromo-6-methoxynaphthalene (47.75 g) was dissolved in dichloromethane(400 ml). To the solution was added acetylchloride (16 ml), and themixture was cooled to 0° C. To the mixture was added aluminum chloride(32 g) over a period of 30 min, and the mixture was stirred at 0 C for 2h. The reaction mixture was added to a mixture of ice water and aqueoussolution of hydrochloric acid. The organic layer was separated and theaqueous layer was extracted with ethyl acetate. The combined extract waswashed with saturated sodium chloride solution, dried and concentrated.The residue was washed with hexane-ethyl acetate to give the titledcompound (53.24 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 2.63 (3H, d, J=0.8 Hz), 3.98 (3H, s), 7.30 (1H, d,J=8.8 Hz), 7.53 (1H, dd, J=1.7, 9.2 Hz), 7.62–7.70 (1H, m), 7.79 (1H, d,J=9.2 Hz), 7.94 (1H, d, J=1.7 Hz)

IR (KBr): 3005, 1686, 1586, 1499, 1254, 1080 cm⁻¹

(ii) Production of 1-(6-bromo-2-methoxynaphthalen-1-yl)ethanol.

1-Acetyl-6-bromo-2-methoxynaphthalene (20.03 g) was dissolved inmethanol (400 ml). To the solution was added sodium borohydride (3.91g), and the mixture was stirred at room temperature for 2 h. To thereaction mixture was added water, and the mixture was concentrated andextracted with ethyl acetate. The organic layer was washed with waterand saturated solution of sodium chloride, dried and concentrated. Theresidue was crystallized from hexane-cyclohexane to give the titledcompound (20.09 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 1.64 (3H, d, J=6.6 Hz), 3.76 (1H, d, J=5.2 Hz), 4.01(3H, s), 5.70 (1H, m), 7.29 (1H, d, J=9.2 Hz), 7.52 (1H, dd, J=9.2, 2.2Hz), 7.78 (1H, d, J=9.2 Hz), 7.93 (1H, d, J=2.2 Hz), 8.02 (1H, d, J=9.2Hz)

IR (KBr): 3412, 2971, 1588, 1497, 1248, 1078 cm⁻¹

(iii) Production of[1-(6-bromo-2-methoxynaphthalen-1-yl)ethoxy]-tert-butyldimethylsilane.

1-(6-Bromo-2-methoxynaphthalen-1-yl)ethanol (18.57 g) andtert-butyldimethylchlorosilane (11.40 g) were dissolved in DMF (300 ml).To the solution was added imidazole (13.20 g), and the mixture wasstirred at room temperature for 14 h. The reaction mixture wasconcentrated, and to the residue were added water and ethyl acetate. Theorganic layer was washed with water and saturated solution of sodiumchloride, dried and concentrated to give the titled compound (25.58 g)as a colorless liquid.

¹H-NMR (CDCl₃) δ: −0.27 (3H, s), 0.00 (3H, s), 0.81 (9H, s), 1.56 (3H,d, J=6.8 Hz), 3.91 (3H, s), 5.88 (1H, q, J=6.8 Hz), 7.19 (1H, d, J=8.8Hz), 7.44 (1H, dd, J=9.4, 2.2 Hz), 7.60 (1H, d, J=8.8 Hz), 7.87 (1H, d,J=2.2 Hz), 8.69 (1H, d, J=9.4 Hz)

IR (KBr): 2955, 2928, 1588, 1497, 1250, 1094 cm⁻¹

(iv) Production of[5-[1-(tert-butyldimethylsilyloxy)-ethyl]-6-methoxynaphthalen-2-yl]-(1-trityl-1H-imidazol-4-yl)methanol

In a similar manner to that described in Example 1-(i), the reaction of4-formyl-1-trityl-1H-imidazole (17.10 g) with(1-(6-bromo-2-methoxynaphthalen-1-yl)ethoxy-tert-butyldimethylsilane(21.70 g) was carried out to give the titled compound (15.25 g) as acolorless solid.

¹H-NMR (CDCl₃) δ: −0.28 (3H, s), 0.00 (3H, s), 0.81 (9H, s), 1.58 (3H,d, J=6.6 Hz), 1.62 (3H, s), 3.17 (1H, m), 3.92 (3H, s), 5.84–5.96 (2H,m), 6.64 (1H, s), 7.04–7.45 (18H, m), 7.78 (1H, d, J=8.8 Hz), 7.74–7.82(1H, m), 8.74 (1H, d, J=9.0 Hz)

IR (KBr): 2928, 1248, 1092, 1065, 833, 702 cm⁻¹

(v) Production of[5-[1-(tert-butyldimethylsilyloxy)ethyl]-6-methoxynaphthalen-2-yl]-(1-trityl-1H-imidazol-4-yl)ketone

In a similar manner to that described in Example 1-(ii), a reaction wascarried out by using[5-[1-(tert-butyldimethylsilyloxy)ethyl]-6-methoxynaphthalen-2-yl]-(1-trityl-1H-imidazol-4-yl)methanol(12.65 g) to give the titled compound (11.72 g).

¹H-NMR (CDCl₃) δ: −0.26 (3H, s), 0.01 (3H, s), 0.82 (9H, s), 1.60 (3H,d, J=6.6 Hz), 3.96 (3H, s), 5.91 (1H, q, J=6.6 Hz), 7.06–7.45 (16H, m),7.58 (1H, s), 7.76 (1H, s), 7.84 (1H, d, J=9.2 Hz), 8.16 (1H, dd, J=9.2,1.4 Hz), 8.81–8.93 (2H, m)

IR (KBr): 2955,1618, 1254, 1171, 1092, 1067 cm⁻¹

(vi) Production of[5-[1-(tert-butyldimethylsilyloxy)-ethyl]-6-methoxynaphthalen-2-yl]-(1H-imidazol-4-yl)ketone.

[5-[1-(tert-butyldimethylsilyloxy)ethyl]-6-methoxynaphthalen-2-yl]-(1-trityl-1H-imidazol-4-yl)ketone(5.18 g) and pyridine hydrochloride (1.59 g) were dissolved in methanol(50 ml). The solution was stirred at 50° C. for 1 h. The reactionmixture was concentrated, and water and ethyl acetate were added. Theorganic layer was washed with saturated aqueous solution of sodiumhydrogencarbonate and saturated sodium chloride solution, dried andconcentrated. The obtained residue was washed with ether to give thetitled compound (2.71 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: −0.23 (3H, s), 0.05 (3H, s), 0.84 (9H, s), 1.63 (3H,d, J=6.6 Hz), 3.99 (3H, s), 5.95 (1H, q, J=6.6 Hz), 7.31 (1H, d, J=9.2Hz), 7.83–8.03 (4H, m), 8.49 (1H, s), 8.97 (1H, d, J=9.2 Hz)

IR (KBr): 2928, 1620, 1321, 1254, 1094, 1067, 831 cm⁻¹

(vii) Production of1-[5-[1-(tert-butyldimethylsilyloxy)ethyl]-6-methoxynaphthalen-2-yl]-1-(1H-imidazol-4-yl)-2-methyl-1-propanol.

In a similar manner to that described in Example 1-(ii), a reaction wascarried out by using(5-(1-(tert-butyldimethylsilyloxy)ethyl)-6-methoxynaphthalen-2-yl)(1H-imidazol-4-yl)ketone(1.20 g) to give the titled compound (0.53 g) as an amorphous product.

¹H-NMR (CDCl₃) δ: −0.29 (3H, s),−0.01 (3H, s), 0.70–0.90 (12H, m), 0.99(3H, d, J=7.0 Hz), 1.58 (½×3H, d, J=6.6 Hz), 1.59 (½×3H, d, J=6.6 Hz),2.60–2.78 (1H, m), 3.90 (3H, s), 5.88 (½×1H, q, J=6.6 Hz), 5.89 (½×1H,q, J=6.6 Hz), 7.00 (1H, d, J=8.3 Hz), 7.16 (1H, d, J=9.0 Hz), 7.42–7.58(2H, m), 7.69 (1H, d, J=9.6 Hz), 7.91 (1H, d, J=8.3 Hz), 8.71 (1H, d,J=9.0 Hz)

IR (KBr): 3094, 2957, 1472, 1250, 1067, 1092, 833 cm⁻¹

EXAMPLE 28 Production of1-[5-(1-hydroxyethyl)-6-methoxynaphthalen-2-yl]-1-[1H-imidazol-4-yl]-2-methyl-1-propanol

1-[5-[1-(tert-Butyldimethylsilyloxy)ethyl]-6-methoxynaphthalen-2-yl]-1-(1H-imidazol-4-yl)-2-methyl-1-propanol(0.499 g) was dissolved in THF (5 ml). To the solution was addedtetrabutylammonium fluoride (1.0M in THF; 5 ml), and the mixture wasstirred at 60° C. for 8 h. The reaction mixture was concentrated. Theobtained residue was purified by silica gel column chromatography(eluent, ethyl acetate:methanol=1:0→10:1) and washed with hexane to givethe titled compound (0.24 g) as an amorphous product.

¹H-NMR (CDCl₃) δ: 0.79 (3H, d, J=6.7 Hz), 0.99 (3H, d, J=6.7 Hz), 1.63(3H, d, J=6.6 Hz), 2.54–2.76 (2H, m), 3.99 (3H, s), 5.68 (1H, q, J=6.6Hz), 6.95 (1H, d, J=1.2 Hz), 7.19–7.29 (1H, m), 7.42 (1H, s), 7.56 (1H,d, J=9.0 Hz), 7.75 (1H, d, J=9.0 Hz), 7.94–8.06 (2H, m)

IR (KBr): 3148, 2969, 1464, 1456, 1248, 1078 cm⁻¹

EXAMPLE 29 Production of1-(6-benzyloxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

(i) Production of (6-benzyloxynaphthalen-2-yl)(1H-imidazol-4-yl)ketone

In a similar manner to that described in Example 27-(vi), a reaction wascarried out by using(6-benzyloxynaphthalen-2-yl)(1-trityl-1H-imidazol-4-yl)ketone (82.77 g)to give the titled compound (46.62 g) as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 5.27 (2H, s), 7.28–7.57 (7H, m), 7.88–8.16 (5H, m),8.81 (1H, s)

IR (KBr): 3146, 1626, 1478, 1173, 1011 cm⁻¹

(ii) Production of1-(6-benzyloxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

In a similar manner to that described in Example 1-(iv), a reaction wascarried out by using(6-benzyloxynaphthalen-2-yl)(1H-imidazol-4-yl)ketone (46.50 g) to givethe titled compound (38.02 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.80 (3H, d, J=6.9 Hz), 1.00 (3H, d, J=6.9 Hz), 2.69(1H, m), 5.16 (2H, s), 6.98 (1H, s), 7.13–7.76 (11H, m), 7.96 (1H, s)

IR (KBr): 2967, 1605, 1264, 1221, 1171, 735 cm⁻¹

EXAMPLE 30 Production of1-(1H-imidazol-4-yl)-1-[6-methoxy-5-(propen-2-yl)naphthalen-2-yl]-2-methyl-1-propanol

(i) Production of 2-bromo-6-methoxy-5-(propen-2-yl)naphthalene.

Methyltriphenylphosphonium bromide (35.75 g) was added to THF (200 ml),and potassium t-butoxide (12.34 g) was slowly added to the mixture underice cooling, and the mixture was stirred at room temperature for 15 min.To the mixture was added 1-acetyl-6-bromo-2-methoxynaphthalene (25.05g), and the mixture was stirred at room temperature for 3 h. To thereaction mixture was added water, and the mixture was washed with waterand saturated sodium chloride solution, dried and concentrated. To theobtained residue was added hexane, and insoluble materials were filteredoff. The filtrate was concentrated under reduced pressure to give thetitled compound (23.12 g) as a colorless oil.

¹H-NMR (CDCl₃) δ: 2.10 (3H, d, J=1.4 Hz), 3.94 (3H, s), 4.94 (1H, m),5.52 (1H, m), 7.23–7.35 (1H, m), 7.47 (1H, dd, J=9.2, 2.2 Hz), 7.68 (1H,d, J=9.2 Hz), 7.83 (1H, d, J=9.0 Hz), 7.93 (1H, d, J=2.2 Hz)

IR (KBr): 2940, 1586, 1495, 1260, 1080 cm⁻¹

(ii) Production of[6-methoxy-5-(propen-2-yl)naphthalen-2-yl]-(1-trityl-1H-imidazol-4-yl)methanol

In a similar manner to that described in Example 1-(i), the reaction of4-formyl-1-trityl-1H-imidazole (23.30 g) with2-bromo-6-methoxy-5-(propen-2-yl)naphthalene (23.12 g) was carried outto give the titled compound (19.06 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 2.10 (3H, s), 3.93 (3H, s) 4.92 (1H, m), 5.50 (1H, m),5.89 (1H, s), 6.63 (1H, s), 7.04–7.18 (6H, m), 7.21–7.45 (12H, m), 7.72(1H, d, J=8.8 Hz), 7.81 (1H, s), 7.87 (1H, d, J=8.8 Hz)

IR (KBr): 3063, 1595, 1445, 1260, 1080 cm⁻¹

(iii) Production of[6-methoxy-5-(propen-2-yl)naphthalen-2-yl](1-trityl-1H-imidazol-4-yl)ketone

In a similar manner to that described in Example 1-(ii), a reaction wascarried out by using[6-methoxy-5-(propen-2-yl)naphthalen-2-yl]-(1-trityl-1H-imidazol-4-yl)methanol(17.49 g) to give the titled compound (14.56 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 2.12 (3H, s), 3.97 (3H, s), 4.95 (1H, s), 5.53 (1H,s), 7.10–7.24 (6H, m), 7.25–7.43 (10H, m), 7.58 (1H, d, J=1.6 Hz), 7.76(1H, d, J=1.6 Hz), 7.90 (1H, d, J=9.0 Hz), 7.99 (1H, d, J=9.2 Hz), 8.20(1H, dd, J=9.2, 1.8 Hz), 8.92 (1H, s)

IR (KBr): 2938, 1615, 1520, 1262, 1173, 1078 cm⁻¹

(iv) Production of(1H-imidazol-4-yl)[6-methoxy-5-(propen-2-yl)naphthalen-2-yl]ketone

In a similar manner to that described in Example 27-(vi), a reaction wascarried out by using[6-methoxy-5-(propen-2-yl)naphthalen-2-yl]-(1-trityl-1H-imidazol-4-yl)ketone(13.96 g) to give the titled compound (5.69 g) as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 2.06 (3H, s), 3.93 (3H, s), 4.88 (1H, m), 5.50 (1H,m), 7.53 (1H, d, J=9.2 Hz), 7.89–7.99 (3H, m), 8.03 (1H, dd, J=9.0, 1.8Hz), 8.11 (1H, d, J=9.2 Hz), 8.81 (1H, s)

IR (KBr): 2843, 1640, 1605, 1260, 1076 cm⁻¹

(v) Production of1-(1H-imidazol-4-yl)-1-[6-methoxy-5-(propen-2-yl)naphthalen-2-yl]-2-methyl-1-propanol

In a similar manner to that described in Example 1-(iv), a reaction wascarried out by using(1H-imidazol-4-yl)[6-methoxy-5-(propen-2-yl)naphthalen-2-yl]ketone (3.00g) to give the titled compound (1.23 g) as an amorphous product.

¹H-NMR (CDCl₃) δ: 0.80 (3H, d, J=6.8 Hz), 0.99 (3H, d, J=6.8 Hz), 2.09(3H, s), 2.56–2.80 (1H, m), 3.92 (3H, s), 4.92 (1H, d, J=1.2 Hz), 5.48(1H, d, J=1.2 Hz), 6.96 (1H, s), 7.24 (1H, d, J=8.8 Hz), 7.43 (1H, m),7.52 (1H, dd, J=8.8, 2.0 Hz), 7.73 (1H, d, J=8.8 Hz), 7.87 (1H, d, J=8.8Hz), 7.96 (1H, s)

IR (KBr): 2969, 1497, 1258, 1080, 909, 824, 733 cm⁻¹

EXAMPLE 31 Production of1-(1H-imidazol-4-yl)-1-[6-methoxy-5-(propan-2-yl)naphthalen-2-yl]-2-methyl-1-propanol

1-(1H-Imidazol-4-yl)-1-[6-methoxy-5-(propen-2-yl)naphthalen-2-yl)-2-methyl-1-propanol(0.509 g) was dissolved in methanol (40 ml). To the solution was added10% palladium carbon (0.260 g), and the mixture was stirred at roomtemperature for 5 h under hydrogen atmosphere (3 atoms). The catalystwas filtered off, and concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (eluent,dichloromethane:methanol=50:1→20:1) to give the titled compound (0.234g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.81 (3H, d, J=6.8 Hz), 1.00 (3H, d, J=6.8 Hz), 1.43(3H, d, J=7.2 Hz), 1.44 (3H, d, J=7.0 Hz), 2.60–2.80 (1H, m), 3.80–3.96(4H, m), 6.97 (1H, d, J=0.8 Hz), 7.22 (1H, d, J=8.8 Hz), 7.45 (1H, m),7.54 (1H, dd, J=9.2, 2.0 Hz), 7.67 (1H, d, J=8.8 Hz), 7.95 (1H, d, J=2.0Hz), 8.06 (1H, d, J=9.2 Hz)

IR (KBr): 3077, 2961, 1597, 1464, 1265, 1248, 820 cm⁻¹

EXAMPLE 32 Production of6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl)naphthalen-2-yloxymethyl2,2-dimethylpropionate

(i) Production of6-[1-hydroxy-1-(1-trityl-1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yloxymethyl2,2-dimethylpropionate

Sodium hydride (60% oil dispersion, 0.120 g) was added to DMF (15 ml),and to the mixture was slowly added1-(6-hydroxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol(1.397 g) under ice cooling, and the mixture was stirred for 30 minunder ice cooling. To the mixture was added iodomethyl pivalate (0.83g), and the mixture was stirred at room temperature for 6 h. To themixture were added water and ethyl acetate, and the organic layer waswashed with water and saturated solution of sodium chloride. The extractwas dried and concentrated. The obtained residue was purified by silicagel column chromatography (eluent, hexane:ethyl acetate=5:1→3:1).Recrystallization from hexane-ethyl acetate to give the titled compound(0.433 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.74 (3H, d, J=6.8 Hz), 0.95 (3H, d, J=6.8 Hz), 1.22(9H, s), 2.44–2.62 (1H, m), 3.65 (1H, s), 5.87 (1H, s), 6.80 (1H, d,J=1.6 Hz), 7.06–7.24 (7H, m), 7.25–7.40 (11H, m), 7.55 (1H, dd, J=8.8,1.6 Hz), 7.66 (1H, d, J=8.8 Hz), 7.73 (1H, d, J=9.0 Hz), 7.96 (1H, m)

IR (KBr): 2973, 1748, 1480, 1115, 702 cm⁻¹

(ii) Production of6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yloxymethyl2,2-dimethylpropionate

6-[1-Hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]naphthalen-2-yloxymethyl2,2-dimethylpropionate (0.381 g) was dissolved in acetic acid (15 ml).To the solution was added palladium carbon (0.200 g), and the mixturewas stirred at 50° C. for 2 h under hydrogen atmosphere. The catalystwas filtered off, and the filtrate was concentrated under reducedpressure. To the residue was added ethyl acetate, and the mixture waswashed with saturated aqueous solution of sodium hydrogencarbonate andsaturated sodium chloride solution. The organic layer was dried andconcentrated. The obtained residue was purified by silica gel columnchromatography (eluent, dichloromethane:methanol=30:1→20:1) to give thetitled compound (0.107 g) as an amorphous product.

¹H−NMR (CDCl₃) δ: 0.80 (3H, d, J=6.8 Hz), 1.00 (3H, d, J=6.8 Hz), 1.21(9H, s), 2.58–2.78 (1H, m), 5.86 (2H, s), 6.97 (1H, d, J=0.8 Hz), 7.18(1H, dd, J=8.8, 2.6 Hz), 7.32 (1H, s), 7.44 (1H, d, J=0.8 Hz), 7.58 (1H,dd, J=8.8, 1.8 Hz), 7.67 (1H, d, J=8.8 Hz), 7.74 (1H, d, J=8.8 Hz), 7.98(1H, m)

IR (KBr): 3063, 2971, 1744, 1154, 1028 cm⁻¹

EXAMPLE 33 Production of1-(6-isopropoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

(i) Production of1-(6-isopropoxynaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

In a similar manner to that described in Example 31-(i), the reaction of1-(6-hydroxynaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(0.965 g) with isopropyl iodide (0.20 ml) was carried out to give thetitled compound (0.548 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.75 (3H, d, J=6.8 Hz), 0.94 (3H, d, J=6.8 Hz), 1.39(6H, d, J=6.0 Hz), 2.42–2.60 (1H, m), 3.64 (1H, s), 4.58–4.75 (1H, m),6.79 (1H, d, J=1.4 Hz), 7.01–7.40 (18H, m), 7.51 (1H, dd, J=8.6, 1.7Hz), 7.56–7.73 (2H, m), 7.92 (1H, d, J=1.7 Hz)

IR (KBr): 2975, 1603, 1495, 1262, 1184, 702 cm⁻¹

(ii) Production of1-(6-isopropoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

1-(6-Isopropoxynaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(0.438 g) was dissolved in a mixture of acetic acid (20 ml) and water(0.5 ml), and the solution was stirred at 50° C. for 18 h. The solventwas evaporated, and to the mixture was added ethyl acetate. The mixturewas washed with saturated aqueous solution of sodium hydrogencarbonateand saturated sodium chloride solution. The organic layer was dried andconcentrated. The obtained residue was purified by silica gel columnchromatography (eluent, dichloromethane:methanol=40:1→20:1) to give thetitled compound (0.170 g) as an amorphous product.

¹H-NMR (CDCl₃) δ: 0.80 (3H, d, J=6.9 Hz), 0.99 (3H, d, J=6.9 Hz), 1.38(6H, d, J=6.2 Hz), 2.58–2.78 (1H, m), 4.59–4.75 (1H, m), 6.95 (1H, s),7.03–7.16 (2H, m), 7.44 (1H, s), 7.48–7.76 (3H, m), 7.93 (1H, s)

IR (KBr): 3393, 2975, 1605, 1387, 1264, 1219, 1115 cm⁻¹

EXAMPLE 34 Production of1-(1H-imidazol-4-yl)-2-methyl-1-(6-propoxynaphthalen-2-yl)-1-propanol

(i) Production of2-methyl-1-(6-propoxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

In a similar manner to that described in Example 31-(i), the reaction of1-(6-hydroxynaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.265 g) with 1-bromopropane (0.24 ml) was carried out to give thetitled compound (0.711 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.74 (3H, d, J=6.6 Hz), 0.94 (3H, d, J=6.6 Hz), 1.07(3H, t, J=7.3 Hz), 1.75–1.97 (2H, m), 2.42–2.62 (1H, m), 3.65 (1H, s),4.02 (2H, t, J=6.6 Hz), 6.79 (1H, d, J=1.2 Hz), 7.06–7.38 (17H, m),7.47–7.74 (4H, m), 7.91 (1H, d, J=1.6 Hz)

IR (KBr): 2965, 1603, 1177, 747, 702 cm⁻¹

(ii) Production of1-(1H-imidazol-4-yl)-2-methyl-1-(6-propoxynaphthalen-2-yl)-1-propanol

In a similar manner to that described in Example 31-(ii), a reaction wascarried out by using2-methyl-1-(6-propoxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(0.660 g) to give the titled compound (0.153 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.79 (3H, d, J=6.6 Hz), 0.99 (3H, d, J=6.6 Hz), 1.06(3H, t, J=7.3 Hz), 1.75–1.94 (2H, m), 2.53–2.78 (1H, m), 4.01 (2H, t,J=6.6 Hz), 6.93 (1H, d, J=1.1 Hz), 7.08–7.16 (2H, m), 7.41 (1H, d, J=1.1Hz), 7.52 (1H, dd, J=8.4, 1.8 Hz), 7.58–7.74 (2H, m), 7.92 (1H, s)

IR (KBr): 3059, 2965, 1605, 1472, 1264, 1175 cm⁻¹

EXAMPLE 35 Production of6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl2,2-dimethylpropionate

(i) Production of6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]naphthalen-2-yl2,2-dimethylpropionate

In a similar manner to that described in Example 31-(i), the reaction of1-(6-hydroxynaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.325 g) with pivalic anhydride (0.77 ml) was carried out in pyridineto give the titled compound (0.940 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.73 (3H, d, J=6.6 Hz), 0.95 (3H, d, J=6.6 Hz), 1.40(9H, s), 2.40–2.62 (1H, m), 3.71 (1H, s), 6.79 (1H, d, J=10. Hz),7.06–7.19 (7H, m), 7.26–7.38 (10H, m), 7.46 (1H, d, J=2.2 Hz), 7.56 (1H,dd, J=8.8, 1.8 Hz), 7.68 (1H, d, J=8.8 Hz), 7.79 (1H, d, J=8.8 Hz), 8.02(1H, s)

IR (KBr): 2971, 1752, 1132, 1111, 702 cm⁻¹

(ii) Production of6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl2,2-dimethylpropionate

In a similar manner to that described in Example 31-(ii), a reaction wascarried out by using6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]naphthalen-2-yl2,2-dimethylpropionate (0.757 g) to give the titled compound (0.388 g)as an amorphous product.

¹H-NMR (CDCl₃) δ: 0.78 (3H, d, J=7.0 Hz), 0.99 (3H, d, J=7.0 Hz), 1.39(9H, s), 2.58–2.76 (1H, m), 6.90 (1H, d, J=1.1 Hz), 7.13 (1H, dd, J=8.7,2.2 Hz), 7.34 (1H, d, J=1.1 Hz), 7.45 (1H, d, J=1.1 Hz), 7.57 (1H, dd,J=8.9, 1.8 Hz), 7.69 (1H, d, J=8.7 Hz), 7.79 (1H, d, J=8.9 Hz), 8.02(1H, brs)

IR (KBr): 3123, 2973, 1748, 1146, 1132, 1111 cm⁻¹

EXAMPLE 36 Production of1-(1H-imidazol-4-yl)-1-(6-ethoxyethoxynaphthalen-2-yl)-2-methyl-1-propanol

(i) Production of1-(6-methoxyethoxynaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

In a similar manner to that described in Example 31-(i), the reaction of1-(6-hydroxynaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.329 g) with bromoethylmethyl ether (0.26 ml) was carried out to givethe titled compound (0.577 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.74 (3H, d, J=7.0 Hz), 0.94 (3H, d, J=7.0 Hz),2.40–2.62 (1H, m), 3.48 (3H, s), 3.66 (1H, s), 3.81 (2H, t, J=4.7 Hz),4.23 (2H, t, J=4.7 Hz), 6.79 (1H, d, J=1.4 Hz), 7.05–7.21 (8H, m),7.23–7.38 (10H, m), 7.52 (1H, dd, J=8.8, 1.4 Hz), 7.62 (1H, d, J=8.8Hz), 7.68 (1H, d, J=9.2 Hz), 7.92 (1H, s)

IR (KBr): 2969, 1605, 1447, 1177, 1123, 702 cm⁻¹

(ii) Production of1-(1H-imidazol-4-yl)-1-(6-methoxyethoxynaphthalen-2-yl)-2-methyl-1-propanol

In a similar manner to that described in Example 32-(ii), a reaction wascarried out by using1-(6-methoxyethoxynaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(0.439 g) to give the titled compound (0.057 g) as an amorphous product.

¹H-NMR (CDCl₃) δ: 0.80 (3H, d, J=6.8 Hz), 1.00 (3H, d, J=6.8 Hz),2.60–2.80 (1H, m), 3.48 (3H, s), 3.76–3.86 (2H, m), 4.16–4.26 (2H, m),6.98 (1H, d, J=1.0 Hz), 7.09 (1H, d, J=2.5 Hz), 7.15 (1H, dd, J=8.8, 2.5Hz), 7.47 (1H, d, J=1.0 Hz), 7.55 (1H, dd, J=8.8, 1.8 Hz), 7.60–7.74(2H, m), 7.95 (1H, m)

IR (KBr): 2930, 1605, 1264, 1221, 1125 cm⁻¹

EXAMPLE 37 Production of1-(6-ethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

(i) Production of (6-ethoxynaphthalen-2-yl)(1-trityl-1H-imidazol-4-yl)ketone

2-Bromo-6-ethoxynaphthalene (5.3 g) was dissolved in THF (40 ml). To thesolution were added magnesium (0.515 g) and methyl iodide (one drop),and the mixture was vigorously stirred to dissolve magnesium. Thereaction mixture was cooled in ice bath, and a solution of4-formyl-1-tritylimidazole (7 g) in THF (80 ml) was added dropwise over30 min, and the mixture was stirred at room temperature for 1 h. To thereaction mixture were added saturated aqueous solution of ammoniumchloride (40 ml) and water (40 ml), and the mixture was extracted withethyl acetate. The extract was washed with saturated sodium chloridesolution, dried over magnesium sulfate and concentrated. The residue waswashed with ethyl acetate to give (6-ethoxynaphthalen-2-yl)(1-trityl-1H-imidazol-4-yl)methanol (6.3 g) as a colorless powder. Theproduct (6.3 g) was dissolved in dichloromethane (120 ml). To thesolution was added manganese dioxide (6 g), and the mixture was stirredat room temperature over night. The reaction mixture was filtered withcelite, and the filtrate was concentrated. The residue was crystallizedfrom THF-ethyl acetate to give the titled compound (5.5 g) as acolorless powder.

¹H-NMR (CDCl₃) δ: 1.40(3H,t,J=7 Hz), 4.08(2H,q,J=7 Hz),7.00–7.35(17H,m), 7.47(1H,d,J=1.4 Hz), 7.60–7.70(3H,m), 8.15(1H,d,J=8.8Hz), 8.84(1H,s).

IR (KBr): 1620, 1520, 1469, 1263, 1182 cm⁻¹.

(ii) Production of1-(6-ethoxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol

(6-ethoxynaphthalen-2-yl) (1-trityl-1H-imidazol-4-yl)ketone (3.0 g) wasdissolved in THF (45 ml). To the solution was added dropwise a solutionof isopropylmagnesium chloride in THF (2 M, 4 ml) under ice cooling. Thereaction mixture was stirred at room temperature for 30 min. To themixture were added saturated aqueous solution of ammonium chloride (20ml) and water (20 ml), and the mixture was extracted with ethyl acetate.The extract was washed with saturated sodium chloride solution, driedand concentrated. The residue was crystallized from ethylacetate-diisopropyl ether to give the titled compound (1.72 g) as acolorless powder. Mother liquor was purified by silica gelchromatography (eluent, hexane-ethyl acetate=1:2) to give the titledcompound (0.43 g).

¹H-NMR (CDCl₃) δ: 0.75(3H,d,J=6.8 Hz), 0.94(3H,d,J=6.8 Hz),1.47(3H,t,J=7 Hz), 2.40–2.60(1H,m), 3.64(1H,s), 4.16(2H,q,J=7 Hz),6.80(1H,s), 7.05–7.45(18H,m), 7.50–7.75(3H,m), 7.93(1H,s).

IR (KBr): 2974, 1603, 1489, 1473, 1394 cm⁻¹.

(iii) Production of1-(6-ethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

1-(6-Ethoxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol(0.60 g) was dissolved in acetic acid (10 ml). To the solution was added10% palladium carbon (0.2 g), and the mixture was stirred under hydrogenatmosphere at 50° C. for 2 h then at 60° C. for 3 h. The catalyst wasfiltered off, filtrate was concentrated to dryness. Recrystallizationfrom THF-ethyl acetate gave the titled compound (0.21 g) as a colorlesspowder.

¹H-NMR (CDCl₃) δ: 0.81(3H,d,J=6.8 Hz), 1.00(3H,d,J=6.8 Hz),1.47(3H,t,J=7 Hz), 2.60–2.80(1H,m), 4.14(2H,q,J=7 Hz), 6.99(1H,s),7.09–7.15(2H,m), 7.49–7.55(2H,m), 7.65(1H,d,J=8.8 Hz), 7.71(1h,d,J=8.8Hz), 7.91(1H,d,J=1.8 Hz).

IR (KBr): 2976, 1633, 1604, 1504, 1473, 1392, 1260, 1219 cm⁻¹.

EXAMPLE 38 Production of1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

(i) Production of ethyl 2,3-dimethoxynaphthalen-6-carboxylate

A solution of lithium diisopropylamide in THF (2M; 65 ml) was dilutedwith THF (100 ml), and the solution was cooled to −78° C. To thesolution was added dropwise a solution of ethyl 1,3-dioxane-3-propanoate(20.12 g) in THF (30 ml), and the mixture was stirred at −78° C. for 1h. To the mixture was added dropwise a solution of3,4-dimethoxybenzaldehyde (17.59 g) in THF (40 ml), and the mixture wasstirred at −78° C. for 1 h. The reaction temperature was allowed to roomtemperature. To the reaction mixture was added saturated aqueoussolution of ammonium chloride, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated sodium chloridesolution, dried and concentrated. The residue was purified by silica gelcolumn chromatography (eluent, hexane:ethyl acetate=2:1) to give ethyl3-(3,4-dimethoxyphenyl)-2-(1,3-dioxane-2-ylmethyl)-3-hydroxypropionate(33.09 g) as an oil. The product was diluted with toluene (400 ml), andto the mixture was added polyphosphoric acid (54 g), and the mixture wasstirred at 100° C. for 15 min. After cooling the reaction mixture, waterwas added. The mixture was extracted with ethyl acetate. The organiclayer was washed with saturated aqueous solution of sodiumhydrogencarbonate and saturated sodium chloride solution, and dried overanhydrous magnesium sulfate. The solvent was distilled off, and theresidue was purified by silica gel column chromatography (eluent,hexane:ethyl acetate=4:1) followed by recrystallization from ethylacetate-hexane to give the titled compound (16.01 g) as a colorlesssolid.

¹H-NMR (CDCl₃) δ: 1.44 (3H, t, J=7.2 Hz), 4.01 (3H, s), 4.02 (3H, s),4.42 (2H, q, J=7.2 Hz), 7.14 (1H, s), 7.21 (1H, s), 7.70 (1H, d, J=8.5Hz), 7.94 (1H, dd, J=8.5, 1.8 Hz), 8.45 (1H, m)

IR (KBr): 2978, 1713, 1489, 1238 cm⁻¹

(ii) Production of (6,7-dimethoxynaphthalen-2-yl)methanol

Lithium aluminum hydride (2.77 g) was added to THF (200 ml) and themixture was cooled to 0° C. To the mixture was slowly added ethyl2,3-dimethoxynaphthalen-6-carboxylate (14.30 g), and the mixture wasstirred at room temperature for 1 h. To the reaction mixture was added1N-hydrochloric acid, and the mixture was extracted with ethyl acetate.The organic layer was dried and concentrated. The residue wascrystallized from ethyl acetate-diisopropyl ether to give the titledcompound (9.73 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 3.99 (3H, s), 4.00 (3H, s), 4.80 (2H, s), 7.10 (1H,s), 7.11 (1H, s), 7.33 (1H, dd, J=8.4, 1.8 Hz), 7.60–7.72 (2H, m)

IR (KBr): 3299, 1514, 1497, 1262, 1161, 856 cm⁻¹

(iii) Production of 6,7-dimethoxy-2-formylnaphthalene

In a similar manner to that described in Example 1-(ii), a reaction wascarried out by using (6,7-dimethoxynaphthalen-2-yl)methanol (9.26 g) togive the titled compound (7.40 g).

¹H-NMR (CDCl₃) δ: 4.04 (6H, s), 7.17 (1H, s), 7.26 (1H, s), 7.76 (1H, d,J=8.4 Hz), 7.83 (1H, dd, J=8.4, 1.6 Hz), 8.19 (1H, m), 10.10(1H,s)

IR (KBr): 1688, 1487, 1211, 1157 cm⁻¹

(iv) Production of(6,7-dimethoxynaphthalen-2-yl)(1H-imidazol-4-yl)ketone

In a similar manner to that described in Example 20-(i), a reaction wascarried out by using 6,7-dimethoxy-2-formylnaphthalene (3.84 g) to givethe titled compound (1.31 g) as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 3.93 (3H, s), 3.94 (3H, s), 7.39 (1H, s), 7.53 (1H,s), 7.80–8.03 (5H, m), 8.72 (1H, brs)

IR (KBr): 3088, 1636, 1508, 1489, 1260, 1159, 883 cm⁻¹

(v) Production of1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

In a similar manner to that described in Example 1-(iv), a reaction wascarried out by using (6,7-dimethoxynaphthalen-2-yl)(1H-imidazol-4-yl)ketone (0.804 g) to give the titled compound (0.613 g)as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.81 (3H, d, J=6.6 Hz), 1.00 (3H, d, J=6.6 Hz),2.60–2.78 (1H, m), 3.96 (3H, s), 3.97 (3H, s), 6.98 (1H, d, J=1.0 Hz),7.07 (1H, s), 7.11 (1H, s), 7.41–7.49 (2H, m), 7.61 (1H, d, J=8.4 Hz),7.89 (1H, d, J=1.4 Hz)

IR (KBr): 3322, 2965, 1510, 1254, 1163, 731 cm⁻¹

EXAMPLE 39 Production of1-(6-methoxy-5-methylnaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

(i) Production of 6-bromo-2-methoxynaphthalen-1-ylmethanol

In a similar manner to that described in Example 27-(ii), a reaction wascarried out by using 6-bromo-1-formyl-2-methoxynaphthalene (4.07 g) togive the titled compound (3.20 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 3.98 (3H, s), 5.14 (2H, s), 7.30 (1H, d, J=9.2 Hz),7.57 (1H, dd, J=2.2, 9.2 Hz), 7.74 (1H, d, J=9.2 Hz), 7.95 (1H, d, J=2.2Hz), 7.99 (1H, d, J=9.2 Hz).

IR (KBr): 3330, 1589, 1503, 1267, 1250 cm⁻¹.

(ii) Production of 6-bromo-2-methoxy-1-methylnaphthalene

6-Bromo-2-methoxynaphthalen-1-ylmethanol (2.05 g) was dissolved in THF(20 ml). To the solution were added triethylamine (3.2 ml) and themixture was cooled to 0° C. To the mixture was addedmethanesulfonylchloride (0.9 ml), and the mixture was stirred at roomtemperature for 1 h. The solvent was distilled off, and, to the reactionmixture were added water and ethyl acetate. The organic layer was washedwith water and saturated solution of sodium chloride, dried andconcentrated, and the residue was dissolved in dimethylsulfoxide (20ml). To the reaction mixture was added sodium iodide (1.49 g), and themixture was stirred at room temperature for 1 h. To the mixture wasadded sodium borohydride (1.09 g), and the mixture was further stirredat room temperature for 1 h. To the reaction mixture was added water andethyl acetate. The organic layer was washed with water and saturatedsolution of sodium chloride, dried and concentrated. The obtainedresidue was purified by silica gel column chromatography (eluent,hexane) to give the titled compound (1.16 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 2.52 (3H, s), 3.94 (3H, s), 7.25 (1H, d, J=9.0 Hz),7.52 (1H, dd, J=1.8, 9.0 Hz), 7.61 (1H, d, J=9.0 Hz), 7.81 (1H, d, J=9.0Hz), 7.92 (1H, d, J=1.8 Hz).

IR (KBr): 1588, 1499, 1264, 1250, 1103, 883 cm⁻¹.

(iii) Production of1-(6-methoxy-5-methylnaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

6-Bromo-2-methoxy-1-methylnaphthalene (0.95 g) was dissolved in THF (15ml). The solution was cooled to −78° C. To the reaction mixture wasadded dropwise a solution of n-butyllithium in hexane (1.6M, 3 ml), andthe mixture was stirred for 15 min. To the mixture was added a solutionof 1-(1H-imidazol-4-yl)-2-methyl-1-propanone (0.155 g) in THF (10 ml),and the temperature of the mixture was elevated to room temperature. Tothe reaction mixture were added aqueous solution of ammonium chlorideand ethyl acetate and the organic layer was separated. The aqueous layerwas extracted with ethyl acetate. The extracts were combined, dried andconcentrated. The residue was purified by silica gel chromatography(eluent, dichloromethane:methanol=20:1) to give the titled compound(0.184 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.81 (3H, d, J=6.8 Hz), 1.01 (3H, d, J=6.8 Hz), 2.52(3H, s), 2.60–2.80 (1H, m), 3.92 (3H, s), 6.98 (1H, d, J=1.0 Hz), 7.24(1H, d, J=9.2 Hz), 7.48 (1H, d, J=1.0 Hz), 7.59 (1H, dd, J=2.0, 9.0 Hz),7.69 (1H, d, J=9.2 Hz), 7.87 (1H, d, J=9.0 Hz), 7.97 (1H, d, J=2.0 Hz).

IR (KBr): 2967, 1267, 1254, 1105, 816 cm⁻¹.

EXAMPLE 40 Production of1-(6-hydroxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

(i) Production of 6-bromo-1-methyl-2-naphthol

6-Bromo-2-methoxy-1-methylnaphthalene (2.70 g) was dissolved indichloromethane (20 ml). The solution was cooled to −70° C., and to thesolution was added a solution of boron tribromide in dichloromethane (1M; 14 ml). The mixture was stirred at room temperature for 1 h. To themixture was added water under ice cooling, and the mixture was extractedwith dichloromethane, washed with water and dried. The solvent wasdistilled off and the residue was purified by column chromatography(eluent, hexane:ethyl acetate=1:1) to give the titled compound (2.55 g)as a pale yellow substance.

¹H-NMR (CDCl₃) δ: 2.50 (3H, s), 5.10 (1H, br s), 7.06 (1H, d, J=8.8 Hz),7.51 (1H, d, J=8.8 Hz),7.53 (1H, dd, J=1.9, 9.0 Hz), 7.76 (1H, d, J=9.0Hz), 7.90 (1H, d, J=1.9 Hz).

IR (KBr): 3245, 1591, 1497, 1356, 1341, 1260, 1198, 1080, 893, 878, 810cm⁻¹.

(ii) Production of2-bromo-6-tert-butyldimethylsilyloxy-5-methylnaphthalene

6-Bromo-1-methyl-2-naphthol (2.40 g),tert-butyldimethylchlorosilane(1.67 g) and 4-dimethylaminopyridine(catalytic amount) were dissolved in THF (30 ml). The solution wasstirred at room temperature for 12 h. The solution was diluted withwater, and extracted with ethyl acetate. The extract was washed withwater, saturated sodium chloride solution, successively. The solvent wasdistilled off and the residue was purified by column chromatography(eluent, hexane) to give the titled compound (3.35 g) as colorlessneedles.

¹H-NMR (CDCl₃) δ: 0.23 (6H, s), 1.06 (9H, s), 2.50 (3H, s), 7.07 (1H, d,J=9.0 Hz), 7.49 (1H, d, J=9.0 Hz), 7.51 (1H, dd, J=2.0, 9.0 Hz), 7.77(1H, d, J=9.0 Hz), 7.90 (1H, d, J=2.0 Hz).

IR (KBr): 2926, 2857, 1470, 1460, 1258, 928, 878, 841, 816, 781 cm⁻¹.

(iii) Production of1-(6-tert-butyldimethylsilyloxy-naphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

2-Bromo-6-tert-butyldimethylsilyloxy-5-methylnaphthalene (3.0 g) wasdissolved in THF (50 ml). The solution was cooled to −70° C. To thesolution was slowly added a solution of n-butyl lithium in hexane (1.6M; 6.4 ml), and the mixture was stirred at −70° C. for 20 min. To themixture was added dropwise a solution of 4-formyl-1-trityl-1H-imidazole(2.71 g) in THF (15 ml). The mixture was stirred for 20 min at −70° C.To the mixture was added water, and the mixture was extracted with ethylacetate, washed with saturated sodium chloride solution and dried. Thesolvent was distilled off and the residue was purified by columnchromatography (eluent, hexane:THF=2:1) followed by recrystallizationfrom isopropyl ether to give the titled compound (4.06 g) as a colorlesspowder.

¹H-NMR (CDCl₃) δ: 0.22 (6H, s), 0.75 (3H, d, J=6.7 Hz), 0.95 (3H, d,J=6.7 Hz), 1.05 (9H, s), 2.47–2.60 (1H, m), 2.50 (3H, s), 3.63 (1H, s),6.80 (1H, d, J=1.4 Hz), 7.03 (1H, d, J=8.8 Hz), 7.11–7.18 (6H, m),7.29–7.37 (10H, m), 7.54 (1H, d, J=2.4 Hz), 7.57 (1H, d, J=1.0 Hz), 7.82(1H, d, J=9.2 Hz), 7.92 (1H, d, J=1.8 Hz).

IR (KBr): 2961, 2930, 1472, 1445, 1242, 934, 839, 747, 702 cm⁻¹.

(iv) Production of1-(6-tert-butyldimethylsilyloxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

In a similar manner to that described in Example 50-(iii), a reactionwas carried out by using1-(6-tert-butyldimethylsilyloxynaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(3.50 g) to give the titled compound (1.76 g) as a colorless powder.

¹H-NMR (CDCl₃) δ: 0.21 (6H, s), 0.81 (3H, d, J=6.8 Hz), 1.0 (3H, d,J=6.6 Hz), 1.05 (9H, s), 2.49 (3H, s), 2.62–2.76 (1H, m), 3.00 (1H, s),6.95 (1H, d, J=1.0 Hz), 7.03 (1H, d, J=9.0 Hz), 7.42 (1H, d, J=1.0 Hz),7.58 (1H, d, J=9.0 Hz), 7.57 (1H, d, J=9.0 Hz), 7.84 (1H, d, J=9.0 Hz),7.94 (1H, d, J=1.8 Hz).

IR (KBr): 3198, 2961, 2930, 1472, 1238, 928, 916, 839, 822, 783 cm⁻¹.

(v) Production of1-(6-hydroxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

To a solution of1-(6-tert-butyldimethylsilyloxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methylpropanol(1.60 g) in THF (10 ml) was added 70% aqueous solution of hydrogenfluoride-pyridine (3 ml) under ice cooling. The mixture was stirred for30 min under ice cooling and for 2 h at room temperature. The mixturewas neutralized with saturated solution of sodium hydrogencarbonate,extracted with dichloromethane and dried. The solvent was distilled offand the residue was purified by column chromatography (eluent,dichloromethane:methanol=10:1→5:1) to give the titled compound (856 mg)as a colorless powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.82 (3H, d, J=6.7 Hz), 0.99 (3H, d, J=6.7 Hz),2.49 (3H, s), 2.70–2.84 (1H, m), 7.01 (1H, d, J=1.4 Hz), 7.09 (11H, d,J=8.9 Hz), 7.54–7.60 (3H,m), 7.82 (1H, d, J=8.9 Hz), 7.89 (1H, d, J=1.8Hz).

IR (KBr): 3218, 2980, 1505, 1468, 1366, 1350, 1269, 1240, 1169, 995, 800cm⁻¹.

EXAMPLE 41 Production of1-(5,6-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

(i) Production of 6-bromo-1-formyl-2-methoxynaphthalene Phosphorylchloride (32.83 g) was added dropwise to DMF (50 ml) at 0° C. Themixture was stirred at room temperature for 30 min. To the mixture wasadded 6-bromo-2-methoxynaphthalene (21.10 g), and the mixture wasstirred at 100° C. for 7 h. To the reaction mixture was added a largeamount of water, and the resulting precipitate was collected byfiltration and washed with water and ethanol. The precipitate was driedand recrystallized from diisopropylether to give the titled compound(6.20 g) as a brown solid.

¹H-NMR (CDCl₃) δ: 4.06 (3H, s), 7.33 (1H, d, J=9.2 Hz), 7.66 (1H, dd,J=2.2, 9.2 Hz), 7.93 (1H, d, J=2.2 Hz), 7.96 (1H, d, J=9.2 Hz), 9.18(1H, d, J=9.2 Hz).

IR (KBr): 1665, 1501, 1269, 1154 cm⁻¹.

(ii) Production of 6-bromo-2-methoxy-1-naphthyl formate

6-Bromo-1-formyl-2-methoxynaphthalene (1.15 g) and m-chloroperbenzoicacid (1.70 g) were dissolved in dichloromethane (100 ml). To thesolution was added anhydrous sodium dihydrogenphosphate (1.59 g), andthe mixture was stirred at room temperature for 16 h. The organic layerwas washed with saturated aqueous solution of sodium hydrogencarbonate,1N-hydrochloric acid and a solution of sodium chloride, successively,dried and concentrated. The obtained residue was washed with hexane togive the titled compound (0.96 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 3.96 (3H, s), 7.36 (1H, d, J=9.0 Hz), 7.56 (1H, dd,J=1.8, 8.8 Hz), 7.68 (1H, d, J=9.0 Hz), 7.72 (1H, d, J=8.8 Hz), 7.97(1H, d, J=1.8 Hz), 8.42 (1H, s).

IR (KBr): 1728, 1591, 1499, 1281, 1177, 1140, 1084 cm⁻¹. (iii)Production of 6-bromo-1,2-dimethoxynaphthalene

6-Bromo-2-methoxy-1-naphthyl formate (0.757 g) was dissolved in amixture of ethanol (8 ml) and water (4 ml). To the solution was addedlithium hydroxide (0.176 g), and the mixture was stirred at 60° C. for 2h. The solvent was distilled off and the residue was dissolved in DMF(10 ml). To the solution were added potassium carbonate (0.483 g) andmethyl iodide (0.5 ml), and the mixture was stirred at room temperaturefor 6 h. To the reaction mixture were added water and ethyl acetate. Theorganic layer was washed with water and saturated solution of sodiumchloride, dried and concentrated. The obtained residue was purified bysilica gel column chromatography (hexane:ethyl acetate=20:1) to give thetitled compound (0.223 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 3.98 (3H, s), 3.99 (3H, s), 7.29 (1H, d, J=8.8 Hz),7.49 (1H, d, J=8.8 Hz), 7.51 (1H, dd, J=1.8, 8.8 Hz), 7.92 (1H, d, J=1.8Hz), 7.99 (1H, d, J=8.8 Hz).

IR (KBr): 1588, 1354, 1273, 1069 cm⁻¹.

(iv) Production of1-(5,6-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol6-Bromo-1,2-dimethoxynaphthalene (2.10 g) was dissolved in THF (30 ml).The solution was cooled to −78° C. To the reaction mixture was addeddropwise a solution of n-butyllithium in hexane (1.6M: 6 ml), and themixture was stirred for 1 h. To the mixture was added a solution of1-(1H-imidazol-4-yl)-2-methyl-1-propanone (0.367 g) in THF (10 ml), andthe temperature of the mixture was elevated to room temperature. To thereaction mixture were added an aqueous solution of ammonium chloride andethyl acetate, and the mixture was extracted with ethyl acetate. Theorganic layer was dried and concentrated. The obtained residue waspurified by silica gel column chromatography(dichloromethane:methanol=20:1) to give the titled compound (0.459 g) asa colorless solid.

¹H-NMR (CDCl₃) δ: 0.80 (3H, d, J=6.8 Hz), 1.00 (3H, d, J=6.8 Hz),2.60–2.80 (1H, m), 3.96 (3H, s), 6.97 (1H, d, J=1.1 Hz), 7.24 (1H, d,J=8.8 Hz), 7.46 (1H, d, J=1.1 Hz), 7.56 (1H, dd, J=1.8, 8.8 Hz), 7.98(1H, d, J=1.8 Hz), 8.02 (1H, d, J=8.8 Hz).

IR (KBr): 2969, 1360, 1270, 1100, 1061, 733 cm⁻¹.

EXAMPLE 42 Production of6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-3-methoxy-2-naphthol

(i) Production of ethyl 6-hydroxy-7-methoxy-2-naphthoate

In a similar manner to that described in Example 38-(i), a reaction wascarried out by using 4-benzyloxy-3-methoxybenzaldehyde (24.90 g) to givethe titled compound (3.00 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 1.43 (3H, t, J=7.2 Hz), 4.03 (3H, s), 4.38 (2H, q,J=7.2 Hz), 6.16 (1H, s), 7.21 (1H, s), 7.28 (1H, s), 7.67 (1H, d, J=8.6Hz), 7.87–7.96 (2H, m), 8.45 (1H, s).

IR (KBr): 3382, 1709, 1487, 1267, 1240 cm⁻¹.

(ii) Production of Ethyl 6-benzyloxy-7-methoxy-2-naphthoate

Ethyl 6-hydroxy-7-methoxy-2-naphthoate (2.95 g) and potassium carbonate(2.21 g) were dissolved in DMF (20 ml). To the solution was addeddropwise benzyl bromide (1.5 ml), and the mixture was stirred at roomtemperature for 12 h. To the reaction mixture was added water, andresulting precipitate was filtered off. The filtrate was dissolved inethyl acetate. The solution was washed with water and saturated solutionof sodium chloride, dried and concentrated. The obtained residue wasrecrystallized from diisopropyl ether-hexane to give the titled compound(2.69 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 1.43 (3H, t, J=7.1 Hz), 4.02 (3H, s), 4.42 (2H, q,J=7.1 Hz), 5.29 (2H, s), 7.19 (1H, s), 7.24 (1H, s), 7.30–7.46 (3H, m),7.46–7.55 (2H, m), 7.65 (1H, d, J=8.6 Hz), 7.92 (1H, dd, J=1.7, 8.6 Hz),8.46 (1H, d, J=1.7 Hz).

IR (KBr): 1713, 1487, 1240, 1194, 1165 cm⁻¹.

(iii) Production of (6-benzyloxy-7-methoxynaphthalen-2-yl)methanol

In a similar manner to that described in Example 38-(ii), a reaction wascarried out by using ethyl 6-benzyloxy-7-methoxy-2-naphthoate (2.51 g)to give the titled compound (1.79 g) as a colorless solid.

¹H-NMR (CDCl₃)δ: 4.00 (3H, s), 4.80 (2H, s), 5.27 (2H, s), 7.13 (1H, s),7.16 (1H, s), 7.27–7.44 (4H, m), 7.46–7.54 (2H, m), 7.59–7.69 (2H, m).

IR (KBr) 3310, 1489, 1256, 1161, 856 cm⁻¹.

(iv) Production of 6-benzyloxy-7-methoxy-2-naphthoaldehyde

In a similar manner to that described in Example 1-(ii), a reaction wascarried out by using (6-benzyloxy-7-methoxynaphthalen-2-yl)methanol(1.69 g) to give the titled compound (1.48 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 4.03 (3H, s), 5.13 (2H, s), 7.21 (1H, s), 7.27 (1H,s), 7.30–7.55 (5H, m), 7.70 (1H, d, J=8.4 Hz), 7.80 (1H, dd, J=1.6, 8.4Hz), 8.18 (1H, brs), 10.09 (1H, s).

IR (KBr): 1690, 1485, 1256, 1211, 1155 cm⁻¹.

(v) Production of1-(6-benzyloxy-7-methoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)methanol

In a similar manner to that described in Example 20-(i), a reaction wascarried out by using 6-benzyloxy-7-methoxy-2-naphthoaldehyde (1.33 g) togive the titled compound (1.20 g) as a colorless solid.

¹H-NMR (CDCl₃+CD₃OD) δ: 3.98 (3H, s), 5.26 (2H, s), 5.92 (1H, s), 6.67(1H, m), 7.14 (1H, s), 7.16 (1H, s), 7.30–7.64 (˜8H, m), 7.75 (1H, s).

IR (KBr): 3034, 1510, 1487, 1248 cm⁻¹.

(vi) Production of 6-benzyloxy-7-methoxynaphthalen-2-yl)(1H-imidazol-4-yl)methanone

In a similar manner to that described in Example 1-(ii), a reaction wascarried out by using (6-benzyloxy-7-methoxynaphthalen-2-yl)(1H-imidazol-4-yl)methanol (1.10 g) to give the titled compound (1.05 g)as a colorless solid.

¹H-NMR (CDCl₃+CD₃OD) δ: 4.03 (3H, s), 5.31 (2H, s), 7.23 (1H, s),7.28(1H, s), 7.30–7.56 (5H, m), 7.73 (1H, d, J=8.6 Hz), 7.76–7.94 (2H,m), 8.40 (1H, brs).

IR (KBr): 3034, 1632, 1483, 1256, 1159 cm⁻¹.

(vii) Production of1-(6-benzyloxy-7-methoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

In a similar manner to that described in Example 1-(iv), a reaction wascarried out by using(6-benzyloxy-7-methoxynaphthalen-2-yl)(1H-imidazol-4-yl)methanone (0.998g) to give the titled compound (0.520 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.80 (3H, d, J=6.6 Hz), 1.00 (3H, d, J=6.6 Hz),2.58–2.78 (1H, m), 3.97 (3H, s), 5.24 (2H, s), 6.96 (1H, d, J=1.2 Hz),7.11 (1H, s), 7.13 (1H, s), 7.26–7.58 (8H, m), 7.85 (1H, s).

IR (KBr): 3191, 1507, 1250, 1163, 1005 cm⁻¹.

(viii)Production of6-1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-3-methoxy-2-naphthol

In a similar manner to that described in Example 17, a reaction wascarried out by using1-(6-benzyloxy-7-methoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol(0.320 μg) to give the titled compound (0.238 g) as a colorless solid.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.80 (3H, d, J=6.8 Hz), 1.00 (3H, d, J=6.8 Hz),2.58–2.76 (1H, m), 3.97 (3H, s), 6.99 (1H, d, J=1.0 Hz), 7.10 (1H, s),7.17 (1H, s), 7.38 (1H, dd, J=1.9, 8.7 Hz), 7.49 (1H, d, J=1.0 Hz), 7.55(1H, d, J=8.7 Hz), 7.83 (1H, d, J=1.9 Hz).

IR (KBr): 2969, 1512, 1487, 1252, 1161, 862 cm⁻¹.

EXAMPLE 43 Production of1-(5-hydroxymethyl-6-methoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

In a similar manner to that described in Example 39-(iii), a reactionwas carried out by using (6-bromo-2-methoxynaphthalen-1-yl)methanol(0.790 g) to give the titled compound (0.135 g) as a colorless solid.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.80 (3H, d, J=6.7 Hz), 1.00 (3H, d, J=6.7 Hz),2.59–2.78 (1H, m), 3.97 (3H, s), 5.13 (2H, s), 6.97 (1H, d, J=1.1 Hz),7.27 (1H, d, J=8.8 Hz), 7.46 (1H, d, J=1.1 Hz), 7.59 (1H, dd, J=2.0, 9.2Hz), 7.82 (1H, d, J=9.2 Hz), 7.95 (1H, d, J=2.0 Hz), 8.02 (1H, d, J=8.8Hz).

IR (KBr): 3156, 1252, 1096, 1001, 822 cm⁻¹.

EXAMPLE 44 Production of1-(1H-imidazol-4-yl)-1-[6-methoxy-5-methoxymethyl-naphthalen-2-yl]-2-methyl-1-propanol

(i) Production of 6-bromo-2-methoxy-1-methoxymethylnaphthalene

Sodium hydride (60% oil dispersion, 0.44 g) was suspended in a mixtureof THF (20 ml) and DMF (20 ml), and the suspension was cooled to 0° C.To the suspension was added (6-bromo-2-methoxynaphthalen-1-yl)methanol(2.59 g), and the mixture was stirred for 15 min. To the mixture wasadded methyl iodide (0.70 ml), and the mixture was stirred at roomtemperature for 1 h. The solvent was distilled off under reducedpressure. To the reaction mixture were added ethyl acetate and water,and the organic layer was washed with water and saturated sodiumchloride solution. The organic layer was dried and concentrated. Theobtained residue was recrystallized from hexane-ethyl acetate to givethe titled compound (1.59 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 3.43 (3H, s), 3.96 (3H, s), 4.49 (2H, s), 7.29 (1H, d,J=9.2 Hz), 7.55 (1H, dd, J=2.2, 8.8 Hz), 7.74 (1H, d, J=9.2 Hz),7.91–7.99 (2H, m).

IR (KBr): 2976, 1503, 1265, 1250, 1084 cm⁻¹.

(ii) Production of1-(1H-imidazol-4-yl)-1-[6-methoxy-5-methoxymethyl-naphthalen-2-yl]-2-methyl-1-propanol

In a similar manner to that described in Example 39-(iii), a reactionwas carried out by using 6-bromo-2-methoxy-1-methoxymethylnaphthalene(1.51 g) to give the titled compound (0.293 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.80 (3H, d, J=6.7 Hz), 0.99 (3H, d, J=6.7 Hz),2.58–2.80 (1H, m), 3.44 (3H, s), 3.93 (3H, s), 4.94 (2H, s), 6.90 (1H,s), 7.16–7.30 (1H, m), 7.38 (1H, s), 7.58 (1H, d, J=9.2 Hz), 7.80 (1H,d, J=8.4 Hz), 7.92–8.06 (2H, m).

IR (KBr): 2967, 1271, 1252, 1088, 733 cm⁻¹.

EXAMPLE 45 Production of1-(5-ethyl-6-methoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

(i) Production of 6-bromo-1-ethenyl-2-methoxynaphthalene

A mixture of methyltriphenylphosphonium bromide (2.64 g) and potassiumt-butoxide (0.84 g) in THF (30 ml) was stirred for 2 h under icecooling. To the mixture was added 6-bromo-1-formyl-2-methoxynaphthalene(1.6 g), and the mixture was stirred at room temperature for 1 h. To thereaction mixture was added 1N-hydrochloric acid, and the mixture wasextracted with ethyl acetate. The extract was washed with solution ofsodium chloride, dried and concentrated. The residue was purified bysilica gel chromatography (eluent, hexane-ethyl acetate=20:1) followedby recrystallization from hexane to give the titled compound (0.43 g) asa colorless powder.

¹H-NMR (CDCl₃) δ: 3.96(3H,s), 5.69(1H,dd,J=11.6 Hz,2.0 Hz),5.76(1H,dd,J=5.8 Hz,2.0 Hz), 7.01(1H,d,J=12 Hz),

7.10(1H,d,J=11.6 Hz), 7.29(1H,d,J=9.4 Hz), 7.50(1H,d,J=9.2 Hz, 2.0 Hz),7.68(1H,d,J=9.2 Hz), 7.93(1H,d,J=2 Hz), 8.06(1H,d,J=9.4 Hz).

IR (KBr): 1585, 1496, 1267, 1249 cm⁻¹.

(ii) Production of1-(5-ethenyl-6-methoxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol

6-Bromo-1-ethenyl-2-methoxynaphthalene (1.20 g) was dissolved in THF (12ml). To the solution was added dropwise a solution of n-butyllithium inhexane (1.6M: 3.4 ml) at −70° C., and the mixture was stirred for 30min. A solution of 1-(1H-imidazol-4-yl)-2-methyl-1-propanone (1.73 g) inTHF (10 ml) was stirred for 40 min, and the temperature of the mixturewas elevated to room temperature. To the reaction mixture were added anaqueous solution of ammonium chloride (10 ml) and water (10 ml), and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated sodium chloride solution, dried and concentrated. Theresidue was crystallized from ethyl acetate to give the titled compound(1.28 g) as a colorless powder. Mother liquor was purified by silica gelcolumn chromatography (eluent, hexane-ethyl acetate=1:1) followed byrecrystallization from ethyl acetate-diisopropyl ether to give thetitled compound (0.23 g).

IR (KBr): 2966, 1591, 1494, 1444, 1251, 702 cm⁻¹.

(iii) Production of1-(5-ethyl-6-methoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

1-(5-Ethenyl-6-methoxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol(1.28 g) was dissolved in a mixture of methanol and THF (1:1,50 ml). Tothe solution was added 10% palladium carbon (0.3 g), and the mixture wasstirred at room temperature for 2 h under hydrogen atmosphere. Thecatalyst was filtered off, and the filtrate was concentrated. Theresidue was dissolved in a mixed solution of methanol and THF (3:1,40ml). To the solution was added pyridine hydrochloride (0.65 g), and themixture was stirred at 60 for 3 h. The reaction mixture was concentratedto dryness, and to the residue were added ethyl acetate and1N-hydrochloric acid (20 ml). The organic layer was extracted four timeswith 1N-hydrochloric acid. The aqueous layer was neutralized with anaqueous solution of sodium hydrogencarbonate and extracted with ethylacetate. The organic layer was washed with saturated sodium chloridesolution, dried and concentrated. The residue was purified by silica gelchromatography (eluent, dichloromethane-methanol=10:1) followed bycrystallization from dichloromethane-diisopropyl ether-hexane to givethe titled compound (0.49 g) as a colorless powder.

¹H-NMR (CDCl₃) δ: 0.81(3H,d,J=6.8 Hz),1.00(3H,d,J=6.8 Hz),1.21(3H,t,J=7.5 Hz), 2.71(1H,quint,J=6.8 Hz), 3.60(2H,q,J=7.5 Hz),3.93(3H,s), 6.99(1H,d,J=1.OHz), 7.24(1H,d,J=9.2 Hz), 7.49(1H,d,J=1.OHz),7.58(1H,dd,J=8.8 Hz,2.0 Hz), 7.69(1H,d,J=8.8 Hz), 7.89(1H,d,J=9.2 Hz),7.97(1H,d,J=2 Hz).

IR (KBr): 2966, 1628, 1597, 1502, 1479, 1464, 1261, 1107 cm⁻¹.

EXAMPLE 46 Production of1-(5-ethenyl-6-methoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

1-(5-Ethenyl-6-methoxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol(230 mg) was dissolved in a mixed solution of methanol and THF (3:1.20ml). To the solution was added pyridine hydrochloride (0.12 g), and themixture was stirred at 60° C. for 3 h. The reaction mixture wasconcentrated to dryness, and to the residue were added ethyl acetate and1N-hydrochloric acid (10 ml). The organic layer was extracted four timeswith 1N-hydrochloric acid. The aqueous layer was neutralized with anaqueous solution of sodium hydrogencarbonate and extracted with ethylacetate. The organic layer was washed with saturated sodium chloridesolution, dried and concentrated. The residue was purified by silica gelchromatography (eluent, dichloromethane-methanol=10:1) to give thetitled compound (91 mg).

¹H-NMR (CDCl₃) δ: 0.79(3H,d,J=6.8 Hz), 0.99(3H,d,J=6.8 Hz),2.65(1H,quint,J=6.8 Hz), 3.92(3H,s), 5.65–5.80(2H,m),6.91(1H,d,J=1.OHz), 7.03(1H,d,J=11.6 Hz), 7.11(1H,d,J=11.8 Hz),7.21(1H,d,J=9 Hz), 7.36(1H,s), 7.51(1H,dd,J=9 Hz,2.0 Hz), 7.71(1H,d,J=9Hz), 7.95(1H,d,J=2.0 Hz), 8.09(1H,d,J=9 Hz).

IR (KBr): 2968, 1630, 1591, 1498, 1464, 1269, 1251 cm⁻¹.

EXAMPLE 47 Production of1-(5-bromo-6-methoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

1-(6-Methoxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol(1.0 g) was dissolved in a mixed solution of dichloromethane andmethanol (1:1,10 ml). To the solution was added pyridinium hydrobromideperbromide(0.77 g), and the mixture was stirred at room temperature for6 h. The solvent was distilled off, and to the reside was added water,and the resulting precipitate (0.75 g) was collected to give thebrominated product.

In a similar manner to that described in Example 46, a reaction wascarried out by using the brominated product (0.2 g) to give the titledcompound (89 mg) as a colorless powder.

¹H-NMR (CDCl₃) δ: 0.79(3H,d,J=7 Hz), 0.99(3H,d,J=7 Hz),2.69(1H,quint,J=7 Hz), 4.00(3H,s), 6.97(1H,s), 7.23(1H,d,J=9.2 Hz),7.47(1H,s), 7.65(1H,dd,J=9.2 Hz,1.8 Hz), 7.78(1H,d,J=9.2 Hz),8.02(1H,d,J=1.8 Hz), 8.13(1H,d,J=9.2 Hz).

IR (KBr): 2968, 1628, 1599, 1493, 1273, 1066 cm⁻¹.

EXAMPLE 48 Production of1-(6-fluoromethyloxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

(i) Production of 2-bromo-6-fluoromethyloxynaphthalene

Sodium hydride (60% oil dispersion, 1.03 g) was added to DMF (30 ml). Tothe mixture was added 6-bromo-2-naphthol (4.80 g) under ice cooling, andthe mixture was stirred at for 20 min. To the mixture was added dropwisea solution of bromofluoromethane (3.0 g) in DMF (10 ml). The mixture wasstirred for 1 h under ice cooling. To the mixture was added water (300ml), and the resulting precipitate was collected by filtration, washedwith water and dried. The resulting solid was purified by silica gelchromatography (eluent, hexane:ethyl acetate=1:1) followed byrecrystallization from hexane to give the titled compound (4.55 g) aspale brown plates.

¹H-NMR (CDCl₃) δ: 5.68 (1H, s), 5.95 (1H, s), 7.26 (1H, dd, J=2.5, 8.9Hz), 7.41 (1H, d, J=2.4 Hz), 7.52 (1H, dd, J=2.0, 8.8 Hz), 7.63 (1H, d,J=8.8 Hz), 7.0 (1H, d, J=9.2 Hz), 7.95 (1H, d, J=1.8 Hz).

IR (KBr): 2928, 1590, 1501, 1252, 1204, 1084, 968, 885 cm⁻¹.

(ii) Production of1-(6-fluoromethyloxynaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

2-Bromo-6-fluoromethyloxynaphthalene (2.10 g) was dissolved in ether(100 ml), and the solution was cooled to −70 C. To the solution wasslowly added a solution of n-butyllithium in hexane (1.6 M, 5.7 ml), andthe mixture was stirred at −70° C. for 20 min. To the mixture was addeddropwise a solution of 4-formyl-1-trityl-1H-imidazole (1.58 g) in THF(10 ml). The mixture was stirred for 20 min at −70° C. To the mixturewas added water, and the mixture was extracted with ethyl acetate anddried. The solvent was distilled off and the residue was purified bysilica gel chromatography (eluent, hexane:ethyl acetate=1:1) followed byrecrystallization from diisopropyl ether to give the titled compound(1.73 g) as colorless needles.

¹H-NMR (CDCl₃) δ: 0.73 (3H, d, J=6.6 Hz), 0.95 (3H, d, J=6.6 Hz),2.45–2.59 (1H, m), 3.71 (1H, s), 5.67 (1H, s), 5.95 (1H, s), 6.80 (1H,d, J=1.2 Hz), 7.10–7.17 (6H, m), 7.22 (1H, d, J=2.5, 8.9 Hz), 7.29–7.36(10H, m), 7.42 (1H, d, J=2.4 Hz), 7.55 (1H, dd, J=1.7, 8.7 Hz), 7.68(1H, d, J=8.8 Hz), 7.76 (1H, d, J=9.0 Hz), 8.00 (1H, s).

IR (KBr): 3200, 2967, 1142, 1080, 993, 756, 750, 700 cm⁻¹.

(iii) Production of1-(6-fluoromethyloxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

In a similar manner to that described in Example 50-(ii), a reaction wascarried out by using1-(6-fluoromethyloxynaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.40 g) to give the titled compound (470 mg) as a colorless powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.80 (3H, d, J=6.8 Hz), 1.01 (3H, d, J=6.8 Hz),2.65–2.78 (1H, m), 5.69 (1H, s), 5.96 (1H, s), 7.00 (1H, d, J=1.2 Hz),7.23 (1H, dd, J=2.5, 8.9 Hz), 7.42 (1H, d, J=2.2 Hz), 7.51 (1H, s), 7.58(1H, dd, J=1.8, 8.6 Hz), 7.71 (1H, d, J=8.8 Hz), 7.80 (1H, d, J=8.8 Hz),7.97 (1H, s).

IR (KBr): 3171, 3140, 2980, 1082, 1030, 968, 860, 810 cm⁻¹.

EXAMPLE 49 Production of1-[5,7-dimethyl-6-methoxynaphthalen-2-yl]-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

(i) Production of 5-bromo-1,3-dimethyl-2-methoxybenzene

In a similar manner to that described in Example 44-(i), a reaction wascarried out by using 4-bromo-2,6-dimethylphenol (80.30 g) to give thetitled compound (75.01 g) as an oil.

¹H-NMR (CDCl₃) δ: 2.25 (6H, s), 3.69 (3H, s), 7.14 (2H, s).

IR (KBr): 2940, 1474, 1219, 1171, 1015, 858, 851 cm⁻¹.

(ii) Production of 3,5-dimethyl-4-methoxybenzaldehyde

5-Bromo-1,3-dimethyl-2-methoxybenzene (70.10 g) was dissolved in THF(700 ml). The solution was cooled to −78° C. To the reaction mixture wasadded dropwise n-butyl lithium in hexane (1.62 M, 250 ml), and themixture was stirred for 15 min. To the mixture was added DMF (50 ml),and the temperature of the mixture was elevated to 0° C. To the reactionmixture was added an aqueous solution of ammonium chloride and ethylacetate, and the mixture was extracted with ethyl acetate. The organiclayer was dried and concentrated. To the residue was added ethylacetate. The organic layer was washed with water and saturated solutionof sodium chloride, dried and concentrated to give the titled compound(52.80 g) as an oil.

¹H-NMR (CDCl₃) δ: 2.35 (6H, s), 3.78 (3H, s), 7.56 (2H, s), 9.88 (1H,s).

IR (KBr): 2928, 1694, 1302, 1134, 1011 cm⁻¹.

(iii) Production of ethyl 5,7-dimethyl-6-methoxy-2-naphthoate

In a similar manner to that described in Example 38-(i), a reaction wascarried out by using 3,5-dimethyl-4-methoxybenzaldehyde (49 g) to givethe titled compound (58.01 g) as an oil.

¹H-NMR (CDCl₃) δ: 1.43 (3H, t, J=7.1 Hz), 2.45 (3H, s), 2.59 (3H, s),3.78 (3H, s), 4.42 (2H, q, J=7.1 Hz), 7.60 (1H, s), 7.90 (1H, d, J=8.8Hz), 8.01 (1H, dd, J=1.4, 8.8 Hz), 8.46 (1H, d, J=1.4 Hz).

IR (KBr): 2940, 1717, 1466, 1254, 1238, 1101 cm⁻¹.

(iv) Production of (5,7-dimethyl-6-methoxynaphthalen-2-yl)methanol

In a similar manner to that described in Example 38-(ii), a reaction wascarried out by using ethyl 6-methoxy-5,7-dimethyl-2-naphthoate (57.01 g)to give the titled compound (18.23 g) as an oil.

¹H-NMR (CDCl₃) δ: 2.44 (3H, s), 2.58 (3H,s), 3.78 (3H, s), 4.80 (2H, s),7.42 (1H, m), 7.47 (1H, brs), 7.65 (1H, brs), 7.98 (1H, d, J=8.8 Hz).

IR (KBr): 3277, 2942, 1468, 1238, 1119, 1057, 1003 cm⁻¹.

(v) Production of 5,7-dimethyl-6-methoxy-2-naphthoaldehyde

In a similar manner to that described in Example 1-(ii), a reaction wascarried out by using (6-methoxy-5,7-dimethyl-naphthalen-2-yl)methanol(13.30 g) to give the titled compound, (9.50 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 2.49 (3H, d, J=0.8 Hz), 2.63 (3H, s), 3.82 (3H, s),7.68 (1H, s), 7.90 (1H, dd, J=1.8, 8.8 Hz), 8.01 (1H, dd, J=0.8, 8.8Hz), 8.21 (1H, d, J=1.8 Hz), 10.13 (1H, s).

IR (KBr): 1694, 1466, 1227, 1157 cm⁻¹.

(vi) Production of(1H-imidazol-4-yl)(5,7-dimethyl-6-methoxynaphthalen-2-yl)methanol

In a similar manner to that described in Example 20-(i), a reaction wascarried out by using 5,7-dimethyl-6-methoxy-2-naphthoaldehyde (5.00 g)to give the titled compound (3.61 g) as a colorless solid.

¹H-NMR (CDCl₃)δ: 2.29 (3H, s), 2.44 (3H, s), 3.68 (3H, s), 5.79 (1H, s),6.41 (1H, s), 7.15 (1H, s), 7.20–7.35 (2H, m), 7.58 (1H, s), 7.64 (1H,d, J=8.8 Hz).

IR (KBr): 2936, 1470, 1236, 1057 cm⁻¹.

(vii) Production of1H-imidazol-4-yl-(5,7-dimethyl-6-methoxynaphthalen-2-yl)methanone

In a similar manner to that described in Example 1-(ii), a reaction wascarried out by using(1H-imidazol-4-yl)(5,7-dimethyl-6-methoxynaphthalen-2-yl)methanol (200mg) to give the titled compound (127 mg) as a colorless solid.

¹H-NMR (CDCl₃) δ: 2.50 (3H, s), 2.65 (3H, s), 3.83 (3H, s), 7.68 (1H,s), 7.84 (1H, s), 7.89–8.08 (3H, m), 8.41 (1H, brs).

IR (KBr): 2996, 1645, 1165, 868 cm⁻¹.

(viii)Production of1-(1H-imidazol-4-yl)-1-[5,7-dimethyl-6-methoxynaphthalen-2-yl]-2-methyl-1-propanol

In a similar manner to that described in Example 1-(iv), a reaction wascarried out by using(1H-imidazol-4-yl)(5,7-dimethyl-6-methoxynaphthalen-2-yl)methanone (104mg) to give the titled compound (62 mg) as a colorless solid

¹H-NMR (CDCl₃) δ: 0.80 (3H, d, J=6.9 Hz), 1.00 (3H,d, J=6.9 Hz), 2.43(3H, s), 2.57 (3H, s), 2.60–2.80 (1H, m), 3.76 (3H, s), 6.96 (1H, d,J=1.0 Hz), 7.44 (1H, d, J=1.0 Hz), 7.50 (1H, s), 7.55 (1H, dd, J=1.8,9.0 Hz), 7.83 (1H, d, J=9.0 Hz), 7.91 (1H, d, J=1.8 Hz).

IR (KBr): 2969, 1468, 1236, 1003, 909, 735 cm⁻¹.

EXAMPLE 50 Production of1-(6-bromonaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

(i) Production of 2,6-dibromonaphthalene

To a solution of triphenylphosphine (64.5 g) in acetonitrile (150 ml)was added dropwise bromine (39 g) under ice cooling, and the mixture wasstirred at room temperature for 30 min. To the mixture was added asolution of 6-bromo-2-naphthol (50.0 g) in acetonitrile (100 ml). Themixture was stirred at 70° C. for 2 h. The solvent was distilled off,and the residue was heated at 250° C. for 5 h. The obtained black solidwas dissolved in dichloromethane, washed with 1N-sodium hydroxidesolution and dried. The solvent was distilled off, and to the residuewas added methanol (50 ml). The mixture was subjected to filtration andthe residue was washed with methanol. The resulting solid was purifiedby column chromatography (eluent, hexane:THF=1:1), then recrystallizedfrom ethyl acetate to give the titled compound (17.5 g) as brown plates.

¹H-NMR (CDCl₃) δ: 7.51–7.62 (4H, m), 7.94 (2H, s).

IR (KBr): 1769, 1568, 1481, 1175, 1134, 1065, 964, 885, 853, 816 cm⁻¹.

(ii) Production of1-(6-bromonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

2,6-Dibromonaphthalene (25.0 g) was dissolved in THF (1250 ml). Thesolution was cooled to −50° C. To the solution was slowly added asolution of n-butyllithium in hexane (1.6 M; 57 ml), and the mixture wasstirred at −50° C. for 20 min. To the mixture was added dropwise asolution of 4-formyl-1-trityl-1H-imidazole (22.2 g) in THF (200 ml). Themixture was stirred at 50° C. for 20 min. To the mixture was addedwater, and the organic layer was separated. The aqueous layer wasextracted with ethyl acetate. The organic layers were combined, driedand concentrated. The residue was purified by silica gel chromatography(eluent, hexane:THF=1:1), and recrystallized from hexane-THF to give thetitled compound (31.2 g) as a pale brown powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.72 (3H, d, J=6.7 Hz), 0.95 (3H, d, J=6.7Hz),2.45–2.58 (1H, m), 3.75 (1H, s), 6.80(1H, d, J=1.4 Hz), 7.10–7.15(6H, m), 7.29–7.35 (10H, m), 7.50 (1H, dd, J=1.8, 8.8 Hz), 7.57 (1H, dd,J=1.8, 8.8 Hz), 7.63–7.69 (2H, m), 7.94 (1H, d, J=1.8 Hz), 8.02 (1H, s).

IR (KBr): 3241, 2967, 1493, 1445, 1169, 1017, 826, 812, 756, 747, 700cm⁻¹.

(iii) Production of1-(6-bromonaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

1-(6-Bromonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.0 g) and pyridine hydrochloride (390 mg) were dissolved in methanol(8 ml). The solution was stirred at 60° C. for 2 h. The solution wascooled and neutralized with saturated aqueous solution of sodiumhydrogencarbonate, The solvent was distilled of f and the residue wasfiltered and washed with ethanol. The filtrate was concentrated, and theresidue was purified by silica gel column chromatography (eluent,dichloromethane:methanol=30:1→10:1), then recrystallized from ethylacetate to give the titled compound (454 mg) as a colorless powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.79 (3H, d, J=6.8 Hz), 1.0 (3H, d, J=6.8 Hz),2.68–2.82 (1H, m), 7.02 (1H, d,J=1.2 Hz), 7.49–7.54 (2H, m),7.63 (1H,dd, J=1.8, 8.8 Hz),7.69 (1H, d, J=8.8H),7.72 (1H, d, J=8.8 Hz), 7.96(1H,d,J=2.0 Hz), 8.01 (1H, s).

IR (KBr): 3225, 2965, 1383, 1165, 1134, 1015, 887, 816, 760 cm⁻¹.

EXAMPLE 51 Production of1-(6-aminonaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

(i) Production of1-{6-[(diphenylmethylene)amino]naphthalen-2-yl}-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

1-(6-Bromonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(14.0 g), benzophenonimine (5.18 g),tris(dibenzylideneacetone)dipalladium (440 mg),(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (872 mg) and sodiumt-butoxide (5.72 g) were dissolved in toluene (140 ml). The solution wasstirred at 80° C. for 18 h under argon atmosphere. The solution wascooled, and diluted with ethyl acetate. The mixture was filtered withcelite, the residue was washed with ethyl acetate. The filtrate wasconcentrated and the residue was purified by silica gel chromatography(eluent, hexane:THF=1:1), then recrystallized from hexane-THF (4:1) togive the titled compound (14.3 g) as a yellow powder.

¹H-NMR (CDCl₃) δ: 0.74 (3H, d, J=6.7 Hz), 0.93 (3H, d, J=6.7 Hz),2.42–2.56 (1H, d), 3.65 (1H, br s), 6.79 (1H, d, J=1.4 Hz), 6.87 (1H,dd, J=2.0, 8.6 Hz), 7.10–7.57 (28H, m), 7.76 (1H, d, J=2.0 Hz), 7.80(1H, d, J=1.4 Hz), 7.86 (1H, s).

IR (KBr): 3453, 2969, 1493, 1445, 1256, 1163, 1005, 812, 748 cm⁻¹.

(ii) Production of1-(6-aminonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

1-{6-[(Diphenylmethylene)amino]naphthalen-2-yl}-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.0 g) was dissolved in THF (5 ml)-methanol (5 ml). To the solutionwere added sodium acetate(285 mg) and hydroxylamine hydrochloride(181mg), and the mixture was stirred at room temperature for 20 min. To themixture was added 0.1N-aqueous solution of sodium hydroxide, and themixture was extracted with ethyl acetate, washed with saturated sodiumchloride solution and dried. The solvent was distilled off and theresidue was purified by silica gel chromatography (eluent, hexane:ethylacetate=2:1→1:1) to give the titled compound (720 mg) as a pale redpowder.

¹H-NMR (CDCl₃) δ: 0.75 (3H, d, J=6.8 Hz), 0.93 (3H, d, J=6.8 Hz),2.44–2.57 (1H, m), 3.62 (1H, br s), 6.79 (1H, d, J=1.4 Hz), 6.89–6.94(2H, m), 7.11–7.18 (6H, m), 7.29–7.36 (10H, m), 7.44 (1H, dd, J=1.8, 8.8Hz), 7.50 (1H, d, J=8.8 Hz), 7.61 (1H, d, J=8.4 Hz), 7.86 (1H, d, J=1.2Hz).

IR (KBr): 3596, 3571, 3370, 3092, 2963, 1634, 1485, 1445, 1001, 852,760, 747 cm⁻¹.

(iii) Production of1-(6-aminonaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

In a similar manner to that described in Example 50-(iii), a reactionwas carried out by using1-(6-aminonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(560 mg) to give the titled compound (120 mg) as a pale red powder.

¹H-NMR (CDCl₃) δ: 0.81 (3H, d, J=6.7 Hz), 0.99 (3H, d, J=6.7 Hz),2.63–2.76 (1H, m), 6.92–6.97 (3H, m), 7.44 (1H, dd, J=1.8, 8.8 Hz),7.49–7.54 (2H, m), 7.63 (1H, d, J=8.6 Hz), 7.82 (1H, s).

IR (KBr): 3200, 2967, 1636, 1609, 1508, 1483, 1387, 1294, 1177, 1005,856, 814 cm⁻¹.

EXAMPLE 52

Production ofN-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}acetamide

(i) Production ofN-{6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]naphthalen-2-yl}acetamide

In a similar manner to that described in Example 51-(ii), a reaction wascarried out by using1-{6-[(diphenylmethylene)amino]naphthalen-2-yl}-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(15.0 g) to give1-(6-aminonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanolas a pale yellow oily substance. The product was dissolved indichloromethane(100 ml). To the solution were added pyridine (5.3 ml)and acetic anhydride (4.1 ml), and the mixture was stirred at roomtemperature for 40 min. To the mixture was added saturated solution ofsodium hydrogencarbonate, and the mixture was extracted withdichloromethane and dried, and the solvent was distilled off. Theresidue was recrystallized from ethyl acetate to give the titledcompound (11.6 g) as pale red crystals.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.75 (3H, d, J=6.7 Hz), 0.95 (3H, d, J=6.7 Hz),2.20 (3H, s), 2.57–2.71 (1H, m), 6.87 (1H, d, J=1.4 Hz), 7.10–7.15 (6H,m), 7.32–7.54 (12H, m), 7.68–7.77 (2H, m), 7.92 (1H, s), 8.15 (1H, s),9.60 (1H, br s).

IR (KBr): 3058, 2969, 1686, 1611, 1547, 1493, 1445, 1298, 1011, 766,747, 700 cm⁻¹.

(ii) Production ofN-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}acetamide

In a similar manner to that described in Example 50-(iii), a reactionwas carried out by usingN-{6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]naphthalen-2-yl}acetamide(11.5 g) to give the titled compound (5.52 g) as a pale red powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.79 (3H, d, J=6.8 Hz), 1.0 (3H, d, J=6.8 Hz),2.17 (3H, s), 2.63–2.76 (1H, m), 6.99 (1H, s), 7.43–7.54 (3H, m),7.65–7.74 (2H, m), 7.91 (1H, s), 8.11 (1H, s).

IR (KBr): 3248, 2971, 1669, 1609, 1586, 1557, 1495, 1391, 1296, 818cm⁻¹.

EXAMPLE 53 Production ofN′-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}-N,N-dimethylurea

(i) Production ofN′-{6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]naphthalen-2-yl}-N,N-dimethylurea

In a similar manner to that described in Example 51-(ii), a reaction wascarried out by using1-{6-[(diphenylmethylene)amino]naphthalen-2-yl}-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(3.0 g) to give a crude1-(6-aminonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanolas a pale yellow oil. The product was dissolved in THF (10 ml). To thesolution were added pyridine (1.06 ml) and p-nitrophenyl chlorocarbonate(1.76 g) under ice cooling, and the mixture was stirred for 20 min. Tothe mixture was added water, and the mixture was washed with ethylacetate and saturated sodium chloride solution and dried. And thesolvent was distilled off. The residue was purified by columnchromatography (eluent, ethyl acetate:hexane=2:1), then recrystallizedfrom ethyl acetate-hexane (2:1) to give p-nitrophenylcarbamate compound(1.30 g).

p-Nitrophenylcarbamate compound (1.20 g) was dissolved in DMF (8 mL). Tothe solution were added triethylamine (0.73 mL) and dimethylaminehydrochloride (284 mg), and the mixture was stirred at room temperaturefor 1 h. To the mixture was added 0.1N-aqueous solution of sodiumhydroxide, and the mixture extracted with ethyl acetate, and washed with0.3N aqueous solution of sodium hydroxide, water and saturated sodiumchloride solution, successively, and dried. The solvent was distilledoff and the residue was purified by column chromatography (eluent, ethylacetate), and recrystallized from ethyl acetate-hexane(1:1) to give thetitled compound (745 mg) as a colorless powder.

¹H-NMR (CDCl₃) δ: 0.74 (3H, d, J=6.6 Hz), 0.94 (3H, d, J=6.6 Hz),2.44–2.57 (1H, m), 3.06 (6H, s), 3.70 (1H, br s), 6.46 (1H, s), 6.79(1H, d, J=1.2 Hz), 7.10–7.15 (6H, m), 7.29–7.38 (1H, m), 7.48 (1H, dd,J=1.4, 8.8 Hz), 7.64 (1H, d, J=9.2 Hz), 4.69 (1H, d, J=8.8 Hz), 7.93(2H, s).

IR (KBr): 3368, 2969, 1672, 1609, 1541, 1493, 1385, 1291, 1192, 758,743, 700 cm⁻¹.

(ii) Production ofN′-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}-N,N-dimethylurea

In a similar manner to that described in Example 50-(iii), a reactionwas carried out by usingN′-{6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]naphthalen-2-yl}-N,N-dimethylurea(650 mg) to give the titled compound (246 mg) as a colorless powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.80 (3H, d, J=6.8 Hz), 1.00 (3H, d, J=6.8 Hz),2.67–2.80 (1H, m), 3.06 (6H, s), 7.01 (1H, d, J=1.2 Hz), 7.46 (1H, dd,J=2.2, 8.8 Hz), 7.51–7.56 (2H, m), 7.66 (1H, d, J=8.6 Hz), 7.74 (1H, d,J=8.8 Hz), 7.83 (1H, d, J=1.8 Hz), 7.92 (1H, d, J=1.0 Hz).

IR (KBr): 3200, 2969, 1649, 1535, 1493, 1406, 1387, 1364, 1227, 1194,814 cm⁻¹.

EXAMPLE 54 Production ofN-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}-N′-methylurea

1-(6-Aminonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.40 g) was dissolved in THF (10 ml). To the solution were addedpyridine (0.65 ml) and phenyl chlorocarbonate (0.50 ml) under icecooling, and the mixture was stirred for 30 min. The reaction mixturewas poured into phosphate buffer solution(pH 7.0), and the mixture wasextracted with ethyl acetate, washed with saturated sodium chloridesolution and dried. The solvent was distilled off to givephenylcarbamate compound as a red oil.

The obtained phenylcarbamate compound was dissolved in DMSO (5 ml). Tothe solution were added methylamine hydrochloride (360 mg) and10N-aqueous solution of sodium hydroxide (0.54 ml), and the mixture wasstirred at room temperature for 1 h. To the mixture was added0.5N-aqueous solution of sodium hydroxide, and the mixture was extractedwith ethyl acetate, washed with 0.5N-aqueous solution of sodiumhydroxide and saturated sodium chloride solution, successively, anddried. The solvent was distilled off and the residue was purified bycolumn chromatography (eluent, hexane:ethyl acetate=1:2→1:4) to giveN-{6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]naphthalen-2-yl}-N′-methylurea(984 mg) as a pale yellow powder. In a similar manner to that describedin Example 50-(iii), a reaction was carried out by using the product(850 mg) to give the titled compound (278 mg) as a pale red powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.79 (3H, d, J=6.9 Hz), 0.97 (3H, d, J=6.9 Hz),2.74–2.87 (1H, m), 2.79 (3H, s), 7.03 (1H, s), 7.38 (1H, dd, J=2.2, 8.8Hz), 7.55–7.66 (3H, m), 7.72 (1H, d, J=9.0 Hz), 7.87 (1H, d, J=2.0 Hz),7.94 (1H, s).

IR (KBr): 3320, 2971, 1655, 1555, 1493, 1387, 1341, 1296, 1248, 814cm⁻¹.

EXAMPLE 55 Production ofN-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl]methanesulfonamide

(i) Production ofN-{6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]naphthalen-2-yl}methanesulfonamide

In a similar manner to that described in Example 51-(ii), a reaction wascarried out by using1-{6-[(diphenylmethylene)amino]naphthalen-2-yl}-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(2.0 g) to give crude product containing1-(6-aminonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanolas a pale yellow oily substance. The crude product was dissolved indichloromethane (10 ml). To the solution were added pyridine (0.71 ml)and methanesulfonyl chloride (0.34 ml) under ice cooling, and themixture was stirred for 30 min. To the mixture was added 0.1N-aqueoussolution of sodium hydroxide, and the mixture was extracted with ethylacetate, washed with saturated sodium chloride solution and dried. Thesolvent was distilled off. The residue was purified by columnchromatography (eluent, hexane:ethyl acetate=1:1) to give the titledcompound (1.16 g) as a pale yellow powder.

¹H-NMR (CDCl₃) δ: 0.72 (3H, d, J=6.7 Hz), 0.98 (3H, d, J=6.7 Hz),2.43–2.57 (1H, m), 3.02 (3H, s), 3.70 (s, 1H), 6.84 (1H, d, J=1.4 Hz),7.02 (1H, dd, J=2.2, 8.8 Hz), 7.12–7.19 (6H, m), 7.31–7.40 (10H, m),7.45 (1H, dd, J=1.7, 8.7 Hz), 7.51–7.61 (3H, m), 7.91 (2H, s).

IR (KBr): 3505, 3248, 3148, 2969, 1491, 1447, 1343, 1319, 1152, 978,747, 702 cm⁻¹.

(ii) Production ofN-(6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}methanesulfonamide

In a similar manner to that described in Example 50-(iii), a reactionwas carried out by usingN-{6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]naphthalen-2-yl}methanesulfonamide(900 mg) to give the titled compound (385 mg) as a colorless powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.78 (3H, d, J=6.8 Hz), 1.00 (3H, d, J=6.8 Hz),1.84–1.90 (1H, m), 2.97 (3H, s), 6.98 (1H, s), 7.28 (1H, dd, J=1.9, 8.7Hz), 7.50 (1H, d, J=1.0 Hz), 7.55 (1H, dd, J=1.7, 8.7 Hz), 7.62–7.69(2H, m), 7.74 (1H, d, J=8.7 Hz), 7.95 (1H, s).

IR (KBr): 3214, 2969, 1607, 1481, 1379, 1341, 1308, 1150, 980 cm⁻¹.

EXAMPLE 56 Production of1-(6-hydroxymethylnaphthalen-2-yl)-1-(1H-imidazol-4-yl)2-methyl-1-propanol

(i) Production of6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-ylpropyl]-2-naphthoaldehyde

1-(6-Bromonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(5.0 g) was dissolved in THF (100 ml), and was cooled to −70° C. To thesolution was slowly added a solution of n-butyllithium in hexane (1.6 M;11.7 ml), and the mixture was stirred at −70° C. for 20 min. To themixture was added dropwise a solution of 4-formylmorpholine (1.96 g) inTHF (10 ml), and the mixture was stirred for 30 min. To the mixture wasadded water, the mixture was extracted with ethyl acetate, washed withsaturated sodium chloride solution and dried. The solvent was distilledoff and the residue was purified by column chromatography (eluent,hexane:THF=4:1→2:1), followed by recrystallization from hexane-THF (6:1)to give the titled compound (2.69 g) as a pale yellow powder.

¹H-NMR (CDCl₃) δ: 0.74 (3H, d, J=6.8 Hz), 0.97 (3H, d, J=6.8 Hz),2.48–2.62 (1H, m), 3.79 (1H, br s), 6.83 (1H, d, J=1.4 Hz), 7.10–7.17(6H, m), 7.30–7.36 (10H, m), 7.70 (1H, dd, J=1.7, 8.7 Hz), 7.85–7.96(3H, m), 8.11 (1H, d, J=1.6 Hz), 8.29 (1H, s), 10.14 (1H, s).

IR (KBr): 3256, 2971, 1694, 1628, 1474, 1447, 1161, 1128, 1009, 768,747, 702 cm⁻¹.

(ii) Production of1-(6-hydroxymethylnaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

6-[1-Hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-ylpropyl]-2-naphthoaldehyde(800 mg) was dissolved in THF (6 ml)-ethanol(12 ml). To the solution wasadded sodium borohydride (56 mg). The mixture was stirred at roomtemperature for 30 min. To the mixture was added water, and the mixturewas extracted with ethyl acetate, washed with saturated sodium chloridesolution and dried. The solvent was distilled off and the residue waspurified by column chromatography (eluent, hexane:THF=2:1→1:1) to givethe titled compound (558 mg) as a colorless powder.

¹H-NMR (CDCl₃) δ: 0.73 (3H, d, J=6.9 Hz), 0.96 (3H, d, J=6.9 Hz),2.47–2.61 (1H, m), 3.75 (1H, s), 3.92 (1H, s), 4.82 (2H, s), 6.81 (1H,d, J=1.6 Hz), 7.09–7.16 (6H, m), 7.29–7.38 (10H, m), 7.43 (1H, dd,J=1.6, 8.4 Hz), 7.55 (1H, dd, J=1.8, 8.6 Hz), 7.69–7.80 (3H, m), 8.00(1H, s).

IR (KBr): 3058, 2969, 1493, 1445, 1159, 1130, 1036, 1009, 820, 747, 702cm⁻¹.

(iii) Production of1-(6-hydroxymethylnaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

In a similar manner to that described in Example 50-(iii), a reactionwas carried out by using1-(6-hydroxymethylnaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(500 mg) to give the titled compound (232 mg) as a colorless powder.

¹H-NMR (CDCl₃+CD₃OD) 6:0.79 (3H, d, J=6.7 Hz), 1.00 (3H, d, J=6.7 Hz),2.66–2.79 (1H, m), 4.77 (2H, s), 7.00 (1H, s), 7.44 (1H, dd, J=1.6, 8.4Hz), 7.49 (1H, s), 7.57 (1H, dd, J=1.8, 8.6 Hz), 7.71–7.74 (2H, m), 7.80(1H, d, J=8.4 Hz), 7.98 (1H, m).

IR (KBr): 3200, 2971, 1466, 1385, 1364, 1157, 1128, 1013, 893, 860, 818,743 cm⁻¹.

EXAMPLE 57 Production of1-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}-1-ethanone

(i) Production of1-{6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]naphthalen-2-yl}-1-ethanone

1-(6-Bromonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(7.0 g) was dissolved in THF (150 ml). The solution was cooled to −70°C. To the mixture was slowly added a solution of n-butyl lithium inhexane (1.6 M; 16.4 ml), and the mixture was stirred at −70° C. for 20min. To the mixture was added dropwise a solution ofN-methyl-N-methoxyacetamide (2.45 g) in THF (10 ml), and the mixture wasstirred at −70° C. for 20 min. To the mixture was added water, and themixture was extracted with ethyl acetate, washed with saturated sodiumchloride solution and dried. The solvent was distilled off and theresidue was purified column chromatography (eluent, hexane:THF=6:1→3:1)to give the titled compound (3.53 g) as a colorless powder.

¹H-NMR (CDCl₃) δ: 0.74 (3H, d, J=6.8 Hz), 0.97 (3H, d, J=6.8 Hz),2.48–2.61 (1H, m), 2.72 (3H, s), 3.75 (1H, br s), 6.83 (1H, d, J=1.4Hz), 7.10–7.17 (6H, m), 7.30–7.37 (10H, m), 7.65 (1H, dd, J=1.6, 8.8Hz), 7.84 (1H, d, J=8.8 Hz), 7.87 (1H, d, J=8.8 Hz), 8.01 (1H, dd,J=1.6, 8.8 Hz), 8.07 (1H, s), 8.42 (1H, s).

IR (KBr): 3519, 2963, 1671, 1480, 1445, 1360, 1275, 1265, 1231, 1190,1157, 1140 cm⁻¹.

(ii) Production of1-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}-1-ethanone

In a similar manner to that described in Example 50-(iii), a reactionwas carried out by using1-{6-[1-hydroxy-2-methyl-1-(-1-trityl-1H-imidazol-4-yl)propyl]naphthalen-2-yl}-1-ethanone(350 mg) to give the titled compound (159 mg) as a colorless powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.81 (3H, d, J=6.7 Hz), 1.02 (3H, d, J=6.7 Hz),2.73–2.86 (4H, m), 7.05 (1H, d, J=1.1 Hz), 7.56 (1H, d, J=1.1 Hz), 7.73(1H, dd, J=1.7, 8.7 Hz), 7.89 (1H, d, J=8.7 Hz), 7.92 (1H, d, J=8.7 Hz),7.99 (1H, dd, J=1.7, 8.7 Hz), 8.11 (1H, s), 8.46 (1H, s).

IR (KBr): 3235, 2969, 1672, 1306, 1289, 1044, 895, 824, 789 cm⁻¹.

EXAMPLE 58 Production of1-{6-[1-hydroxy-1-(1H-imidazol-4-yl-2-methylpropyl]naphthalen-2-yl}-1-propanone

(i) Production of1-{6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]naphthalen-2-yl}-1-propanone

In a similar manner to that described in Example 60-(i), the reaction of1-(6-bromonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(2.0 g) with N,N-dimethylpropionamide (688 mg) was carried out to givethe titled compound (824 mg) as a colorless powder.

¹H-NMR (CDCl₃) δ: 0.74 (3H, d, J=6.7 Hz), 0.97 (3H, d, J=6.7 Hz), 1.28(3H, t, J=7.3 Hz), 2.48–2.61 (1H, m), 3.14 (2H, q, J=7.3 Hz), 3.75 (1H,s), 6.82 (1H, d, J=1.2 Hz), 7.11–7.17 (6H, m), 7.30–7.35 (10H, m), 7.65(1H, dd, J=1.6, 8.6 Hz), 7.84 (1H, d, J=8.6 Hz), 7.86 (1H, d, J=8.6 Hz),8.02 (1H, dd, J=1.6, 8.6 Hz), 8.07 (1H, s), 8.44 (1H, s).

IR (KBr): 3214, 2971, 1686, 1495, 1476, 1445, 1383, 1167, 1013, 828,810, 762 cm⁻¹.

(ii) Production of1-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}-1-propanone

In a similar manner to that described in Example 50-(iii), a reactionwas carried out by using1-{6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-propyl]naphthalen-2-yl}-1-propanone(700 mg) to give the titled compound (278 mg) as a colorless powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.80 (3H, d, J=6.7 Hz), 1.02 (3H, d, J=6.7 Hz),1.27 (3H, t, J=7.2 Hz), 2.70–2.83 (1H, m), 3.15 (2H, q, J=7.2 Hz), 7.03(1H, d, J=1.2 Hz), 7.53 (1H, s), 7.69 (1H, dd, J=1.7, 8.8 Hz), 7.87–7.90(2H, m), 8.00 (1H, dd, J=1.7, 8.6 Hz), 8.08 (1H, s), 8.77 (1H, s).

IR (KBr): 3175, 2976, 1684, 1476, 1460, 1433, 1385, 1372, 1348, 1032,901, 818 cm⁻¹.

EXAMPLE 59 Production of1-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}-2-methyl-1-propanone

(i) Production of1-{6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]naphthalen-2-yl}-2-methyl-1-propanone

In a similar manner to that described in Example 57-(i), the reaction of1-(6-bromonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(2.0 g) with 2-methyl-1-(4-morpholinyl)-1-propanone (688 mg) was carriedout to give the titled compound (966 mg) as a colorless powder.

¹H-NMR (CDCl₃) δ: 0.74 (3H, d, J=6.8 Hz), 0.97 (3H, d, J=6.8 Hz), 1.27(6H, d, J=6.8 Hz), 2.48–2.61 (1H, m), 3.69–3.79 (2H, m), 6.82 (1H, d,J=1.2 Hz), 7.10–7.15 (6H, m), 7.31–7.34 (10H, m), 7.65 (1H, dd, J=1.7,8.7 Hz), 7.84 (1H, d, J=8.7 Hz), 7.86 (1H, d, J=8.7 Hz), 8.00 (1H, dd,J=1.7, 8.7 Hz), 8.07 (1H, s), 8.43 (1H, s).

IR (KBr): 3164, 2969, 1682, 1493, 1468, 1445, 1155, 1017, 820, 756, 748,700 cm⁻¹.

(ii) Production of1-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}-2-methyl-1-propanone

In a similar manner to that described in Example 50-(iii), a reactionwas carried out by using1-{6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-propyl]naphthalen-2-yl}-2-methyl-1-propanone(750 mg) to give the titled compound (429 mg) as a colorless powder.

¹H-NMR (CDCl₃) δ: 0.79 (3H, d, J=6.8 Hz), 1.01 (3H, d, J=6.8 Hz), 1.25(6H, d, J=6.8 Hz), 2.65–2.78 (1H, m), 3.64–3.77 (1H, m), 7.00 (1H, d,J=1.0 Hz), 7.47 (1H, s), 7.68 (1H, dd, J=1.8, 8.8 Hz), 7.85 (1H, d,J=8.8 Hz), 7.87 (1H, d, J=8.8 Hz), 7.98 (1H, dd, J=1.8, 8.8 Hz), 8.10(1H, s), 8.41 (1H, s)

IR (KBr): 3069, 2971, 1676, 1628, 1474, 1385, 1221, 1155, 1128, 1017,820 cm⁻¹.

EXAMPLE 60 Production of1-(6-ethylnaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

(i) Production of2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-(6-vinylnaphthalen-2-yl)-1-propanol

A solution of1-(6-bromonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(2.0 g), tetrakis(triphenylphosphine)palladium (116 mg) andtributylvinyltin (1.40 ml) in toluene (30 ml) was refluxed under argonatmosphere for 80 min. The solvent was distilled off and the residue waspurified by column chromatography (eluent, hexane:THF=2:1), thencrystallized from isopropyl ether-hexane (1:1) to give the titledcompound (1.47 g) as a colorless powder.

¹H-NMR (CDCl₃) δ: 0.74 (3H, d, J=6.7 Hz), 0.95 (3H, d, J=6.7 Hz),2.46–2.59 (1H, m), 3.71 (br s, 1H), 5.30 (1H, d, J=10.9 Hz), 5.84 (1H,d, J=17.7 Hz), 6.80 (1H, s), 6.86 (1H, dd, J=10.9, 17.7 Hz), 7.10–7.16(6H, m), 7.29–7.36 (10H, m), 7.52–7.62 (2H, m), 7.69–7.77 (3H, m), 7.98(1H, s).

IR (KBr): 3200, 2969, 1493, 1445, 1165, 1019, 820, 754, 747, 700 cm⁻¹.

(ii) Production of1-(6-ethylnaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol2-Methyl-1-(1-trityl-1H-imidazol-4-yl)-1-(6-vinylnaphthalen-2-yl)-1-propanol(1.20 g) was dissolved in THF (5 ml)-methanol (10 ml). To the solutionwas added 10% palladium carbon (120 mg), and the mixture was stirred atroom temperature for 2 h under hydrogen atmosphere. The catalyst wasfiltered off and washed with THF. The filtrate was concentrated and theresidue was recrystallized from isopropyl ether-hexane (1:1) to give thetitled compound (1.13 g) as a colorless powder.

¹H-NMR (CDCl₃) δ: 0.74 (3H, d, J=6.8 Hz), 0.95 (3H, d, J=6.8 Hz), 1.31(3H, t, J=7.6 Hz), 2.47–2.60 (1H, m), 2.79 (2H, q, J=7.6 Hz), 3.69 (1H,s), 6.80 (1H, s, J=1.4 Hz), 7.09–7.17 (6H, m), 7.27–7.36 (11H, m), 7.53(1H, dd, J=1.8, 8.6 Hz), 7.58 (1H, s), 7.66–7.75 (2H, m), 7.98 (1H, s).

IR (KBr): 3233, 2967, 1493, 1470, 1443, 1171, 1157, 1015, 905, 818, 756,747 cm⁻¹.

(iii) Production of1-(6-ethylnaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

In a similar manner to that described in Example 50-(iii), a reactionwas carried out by using1-(6-ethylnaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(950 mg) to give the titled compound (353 mg) as a colorless powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.80 (3H, d, J=6.7 Hz), 1.00 (3H, d, J=6.7 Hz),1.31 (3H, t, J=7.6 Hz), 2.65–2.85 (3H, m), 6.98 (1H, d, J=1.2 Hz), 7.33(1H, dd, J=1.8, 8.6 Hz), 7.49 (1H, d, J=1.2 Hz), 7.54 (1H, dd, J=1.8,8.6 Hz), 7.58 (1H, s), 7.58–7.77 (2H, m), 7.95 (1H, d, J=1.2 Hz).

IR (KBr): 3231, 2971, 2776, 1458, 1433, 1346, 1238, 1113, 1030, 1019,885, 874 cm⁻¹.

EXAMPLE 61 Production of1-(1H-imidazol-4-yl)-2-methyl-1-(6-methylnaphthalen-2-yl)-1-propanol

(i) Production of2-methyl-1-(6-methylnaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

1-(6-Bromonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(2.0 g), tetramethyltin (0.94 ml), dichlorobis(triphenylphosphine)palladium (70 mg) and lithium chloride (432 mg) were dissolved in DMF(20 ml). The solution was stirred at 80° C. for 17 h. After cooling, thesolution was diluted with water and extracted with ethyl acetate. Theextract was washed with water and saturated sodium chloride solution,successively, and dried. The solvent was distilled off, and the obtainedresidue was purified by silica gel chromatography (eluent,hexane:THF=6:1→4:1),and crystallized from isopropyl ether to give thetitled compound (1.52 g) as colorless needles.

¹H-NMR (CDCl₃) δ: 0.74 (3H, d, J=6.8 Hz), 0.95 (3H, d, J=6.8 Hz),2.46–2.59 (m, 1H), 2.48 (3H, s), 3.70 (1H, br s), 6.80 (1H, d, J=1.2Hz), 7.08–7.17 (6H, m), 7.29–7.36 (11H, m), 7.52 (1H, dd, J=1.8, 8.8Hz), 7.54 (1H, s), 7.63–7.72 (2H, m), 7.96 (1H, s).

IR (KBr): 3258, 2965, 1495, 1445, 1177, 1013, 816, 754, 747, 700 cm⁻¹.

(ii) Production of1-(1H-imidazol-4-yl)-2-methyl-1-(6-methylnaphthalen-2-yl)-1-propanol

In a similar manner to that described in Example 50-(ii), a reaction wascarried out by using2-methyl-1-(6-methylnaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.30 g) to give the titled compound (594 mg) as a colorless powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.80 (3H, d, J=6.8 Hz), 1.00 (3H, d, J=6.8 Hz),2.48 (3H, s), 2.64–2.77 (1H, m), 6.98 (1H, s), 7.28 (1H, dd, J=1.8, 8.3Hz), 7.48–7.56 (2H, m), 7.65–7.74 (2H, m), 7.94 (1H, d, J=1.4 Hz).

IR (KBr): 3171, 2980, 1433, 1127, 1119, 1028, 945, 885, 818 cm⁻¹.

EXAMPLE 62 Production of1-(6-ethynylnaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

(i) Production of1-(6-ethynylnaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

1-(6-Bromonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(3.0 g), trimethylsilylacetylene (1.44 ml),dichlorobis(triphenylphosphine)palladium(182 mg) and copper iodide (99mg) were dissolved in triethylamine-THF (1:1, 50 ml). The solution wasstirred at 60° C. for 24 h. To the solution were addedtrimethylsilylacetylene (0.72 ml), dichlorobis(triphenylphosphine)palladium (91 mg), and copper iodide (45 mg), and the mixture wasstirred at 60° C. for 24 h. The solvent was distilled off, and theresidue was purified by silica gel chromatography (eluent.hexane:THF=2:1) to give a brown oily compound.

The product was dissolved in 1N-sodium hydroxide-methanol-THF (1:1:2, 80ml). The solution was stirred at room temperature for 90 min andconcentrated under reduced pressure. The residue was extracted withethyl acetate washed with saturated sodium chloride solution and dried.The solvent was distilled off, and the residue was purified by silicagel chromatography (eluent, hexane:THF=6:1→4:1) and crystallized fromisopropyl ether to give the titled compound (2.31 g) as a pale yellowpowder.

¹H-NMR (CDCl₃) δ: 0.73 (3H, d, J=6.7 Hz), 0.96 (3H, d, J=6.7 Hz),2.46–2.59 (1H, m), 3.12 (1H, s), 3.74 (1H, br s), 6.80 (1H, d, J=1.4Hz), 7.09–7.7.16 (6H, m), 7.29–7.34 (10H, m), 7.48 (1H, dd, J=1.6, 8.4Hz), 7.57 (1H, dd, J=1.5, 8.7 Hz), 7.67–7.75 (2H, m), 7.96 (1H, s), 8.01(1H, s).

IR (KBr): 3314, 2971, 1493, 1470, 1447, 1169, 1009, 748, 700 cm⁻¹.

(ii) Production of1-(6-ethynylnaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

In a similar manner to that described in Example 50-(ii), a reaction wascarried out by using1-(6-ethynylnaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.30 g) to give the titled compound (583 mg) as a colorless powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.80 (3H, d, J=6.8 Hz), 1.01 (3H, d, J=6.8 Hz),2.67–2.81 (1H, m), 3.20 (1H, s), 7.01 (1H, d, J=1.2 Hz), 7.49 (1H, dd,J=1.6, 8.4 Hz), 7.52 (1H, d, J=1.2 Hz), 7.62 (1H, dd, J=1.8, 8.6 Hz),7.70–7.80 (2H, m), 7.97 (1H, s), 8.01 (1H, s).

IR (KBr): 3316, 3316, 2980, 1460, 1435, 1119, 1030, 903, 816 cm⁻¹.

EXAMPLE 63 Production of1-(1H-imidazol-4-yl)-2-methyl-1-[(6-methylsulfanyl)naphthalen-2-yl)]-1-propanol

(i) Production of O-(6-bromonaphthalen-2-yl)dimethylcarbamothioate

6-Bromo-2-naphthol (44.63 g) was added to a solution of potassiumhydroxide (12.29 g) in water (250 ml) and the mixture was cooled to 0°C. To the mixture was added dropwise a solution ofN,N-dimethylthiocarbamoylchloride (25.30 g) in THF (200 ml), and themixture was stirred at room temperature for 30 min. The reaction mixturewas extracted with ethyl acetate. The organic layer was washed withwater and saturated sodium chloride solution dried and concentrated. Theobtained residue was washed with isopropyl ether to give the titledcompound (43.30 g) as a brown solid.

¹H-NMR (CDCl₃) δ: 3.39 (3H, s), 3.48 (3H, s), 7.27 (1H, dd, J=2.2, 9.2Hz), 7.47 (1H, d, J=2.2 Hz), 7.54 (1H, dd, J=2.0, 8.8 Hz), 7.67 (1H, d,J=8.8 Hz), 7.76 (1H, d, J=9.2 Hz), 8.01 (1H, d, J=2.0 Hz).

IR (KBr): 1541, 1501, 1395, 1289, 1200, 1154, 897 cm⁻¹.

(ii) Production of S-(6-bromonaphthalen-2-yl)dimethylcarbamothioate

O-(6-Mromonaphthalen-2-yl)dimethylcarbamothioate (42.12 g) was dissolvedin diphenylether(300 ml). The solution was stirred at 250˜260° C. for 3h and cooled to room temperature, and diphenylether was distilled off invacuo. To the obtained residue was added isopropyl ether to give thetitled compound (37.10 g) as a brown solid.

¹H-NMR (CDCl₃)δ: 2.90–3.25 (6H, m), 7.51–7.61 (2H, m), 7.68 (1H, d,J=8.8 Hz), 7.75 (1H, d, J=8.6 Hz), 7.94–8.04 (2H, m).

IR (KBr): 1667, 1362, 1098, 866, 689 cm⁻¹.

(iii) Production of 2-bromo-6-(methylsulfanyl)naphthalene

S-(6-Bromonaphthalen-2-yl)dimethylcarbamothioate (13.80 g) was dissolvedin ethanol (90 ml) and water (10 ml). To the solution was addedpotassium hydroxide (3.99 g), and the mixture was heated for 16 h underref lux. The mixture was cooled to 0° C., and to the mixture was addedmethyl iodide (3.6 ml), and the mixture was stirred for 1 h at −78° C.To the reaction mixture was added water, and the resulting precipitatewas filtered off. The filtrate was dissolved in ethyl acetate. Theorganic layer was washed with water and saturated solution of sodiumchloride, dried and concentrated. The obtained residue was purified byshort column chromatography (eluent, hexane-ethyl acetate=10:1) to givethe titled compound (10.89 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 2.58 (3H, s), 7.38 (1H, dd, J=1.8, 8.8 Hz), 7.48–7.68(4H, m), 7.93 (1H, s).

IR (KBr): 1572, 1140, 868, 812 cm⁻¹.

(iv) Production of1-(1H-imidazol-4-yl)-2-methyl-1-(6-methylsulfanylnaphthalen-2-yl)-1-propanol

In a similar manner to that described in Example 39-(iii), a reactionwas carried out by using 2-bromo-6-(methylsulfanyl)naphthalene (0.987 g)to give the titled compound (0.166 g) as a colorless solid.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.79 (3H, d, J=6.8 Hz), 1.00 (3H, d, J=6.8 Hz),2.57 (3H, s), 2.52–2.82 (1H, m), 6.99 (1H, s), 7.35 (1H, d, J=8.4 Hz),7.42–7.80 (5H, m), 7.94 (1H, s).

IR (KBr): 2971, 1491, 1140, 1013, 843 cm⁻¹.

EXAMPLE 64 Production of1-(1H-imidazol-4-yl)-1-(6-methoxy-1-methyl-naphthalen-2-yl)-2-methyl-1-propanol

(i) Production of 6-methoxy-1-methyl-1,2,3,4-tetrahydronaphthalen-1-ol

In a similar manner to that described in Example 2-(i), a reaction wascarried out by using 6-methoxytetralone (25.40 g) to give the titledcompound (27.10 g) as an oil.

¹H-NMR (CDCl₃) δ: 1.54 (3H, m), 1.68–2.00 (4H, m), 2.66–2.81 (2H, m),3.77 (3H, s), 6.58 (1H, d, J=2.9 Hz), 6.77 (1H, dd, J=2.9, 9.0 Hz), 7.49(1H, d, J=9.0 Hz).

IR (KBr): 3349, 2938, 1609, 1501, 1256 cm⁻¹.

(ii) Production of 7-methoxy-4-methyl-1,2-dihydronaphthalene-1-ol

6-Methoxy-1-methyl-1,2,3,4-tetrahydronaphthalen-1-ol(26.90 g) andp-toluenesulfonic acid monohydrate (0.51 g) was dissolved in toluene(200 ml). The solution was heated for 30 min under reflux. The toluenewas distilled off under reduced pressure. The obtained residue waspurified by silica gel chromatography (eluent, hexane:ethylacetate=10:1) to give the titled compound (22.40 g) as an oil.

¹H-NMR (CDCl₃) δ: 1.97–2.05 (3H, m), 2.12–2.30 (2H, m), 2.73 (2H, t,J=8.0 Hz), 3.79 (3H, s), 5.64–5.78 (1H, m), 6.64–6.76 (2H, m), 7.08–7.20(1H, m).

IR (KBr): 2934, 2832, 1497, 1252, 1142, 1034, 824 cm⁻¹.

(iii) Production of 3-bromo-7-methoxy-4-methyl-1,2-dihydronaphthalene

7-Methoxy-4-methyl-1,2-dihydronaphthalene (3.01 g) was dissolved indichloromethane (100 ml). To the solution was added dropwise a solutionof bromine (3.00 g) in dichloromethane (10 ml) over a period of 15 min.To the mixture was added p-dimethylamino pyridine (1.83 g), and themixture was heated for 8 h under reflux, and dichloromethane wasdistilled off under reduced pressure. The obtained residue was purifiedby silica gel chromatography (eluent, dichloromethane) to give thetitled compound (2.34 g) as an oil.

¹H-NMR (CDCl₃) δ: 2.15–2.25 (3H, m), 2.65–2.95 (4H, m), 3.80 (3H, m),6.67 (1H, d, J=2.7 Hz), 6.72 (1H, dd, J=2.7, 8.4 Hz), 7.19 (1H, d, J=8.4Hz).

IR (KBr): 2940, 1495, 1250 cm⁻¹.

(iv) Production of 2-bromo-6-methoxy-1-methylnaphthalene

3-Bromo-7-methoxy-4-methyl-1,2-dihydronaphthalene (2.19 g) and2,3-dichloro-5,6-dicyano-1,4-benzoquinone(DDQ, 2.10 g) were dissolved intoluene (200 ml), and the solution was stirred at 60° C. for 12 h. Thetoluene was distilled off under reduced pressure. The obtained residuewas purified by silica gel chromatography (eluent, hexane) to give thetitled compound (360 mg) as an oil.

¹H-NMR (CDCl₃) δ: 2.76 (3H, s), 3.92 (3H, s), 7.10 (1H, d, J=3.0 Hz),7.18 (1H, dd, J=3.0, 9.2 Hz), 7.44 (1H, d, J=8.9 Hz), 7.56 (1H, d, J=9.2Hz), 7.94 (1H, d, J=8.9 Hz).

IR (KBr): 1624, 1588, 1505, 1410, 1242, 851 cm⁻¹.

(v) Production of1-(1H-imidazol-4-yl)-1-(6-methoxy-1-methyl-naphthalen-2-yl)-2-methyl-1-propanol

In a similar manner to that described in Example 39-(iii), a reactionwas carried out by using 2-bromo-6-methoxy-1-methylnaphthalene (340 mg)to give the titled compound (8 mg) as an amorphous product.

¹H-NMR (CDCl₃) δ: 0.89 (3H, d, J=6.6 Hz), 1.11 (3H, d, J=6.6 Hz), 2.57(3H, s), 2.80–3.02 (1H, m), 3.92 (3H, s), 6.92 (1H, s), 7.07–7.17 (2H,m), 7.52 (1H, s), 7.58 (1H, d, J=9.2 Hz), 7.81 (1H, d, J=9.2 Hz), 7.96(1H, d, J=9.2 Hz).

IR (KBr): 2967, 1624, 1273, 1242, 912, 743 cm⁻¹.

EXAMPLE 65 Production of1-(6-methoxynaphthalen-2-yl)-2-methyl-1-(thiazol-5-yl)-1-propanol

(i) Production of (6-methoxynaphthalen-2-yl)(thiazol-5-yl)methanol

To a solution of 6-methoxynaphthalen-2-ylmagnesium bromide in THF (1.3M; 10 ml) was added dropwise a solution of 5-formylthiazole (1.70 g) inTHF (10 ml) under ice cooling, and the mixture was stirred for 20 minunder ice cooling. The mixture was diluted with saturated aqueoussolution of ammonium chloride, extracted with ethyl acetate, washed withsaturated sodium chloride solution and dried. The solvent was distilledoff and the residue was purified by silica gel chromatography (eluent,hexane:ethyl acetate=2:1→1:1) to give the titled compound (3.47 g) as acolorless powder.

¹H-NMR (CDCl₃)δ: 3.82 (1H, br s), 3.91 (3H, s), 6.17 (1H, s), 7.11–7.19(2H, m), 7.42 (1H, dd, J=1.8, 8.6 Hz), 7.60 (1H, s), 7.68–7.78 (3H, m),8.63 (1H, s).

IR (KBr): 3310, 3077, 1609, 1393, 1269, 1026, 858 cm⁻¹.

(ii) (6-methoxynaphthalen-2-yl)(thiazol-5-yl)ketone

(6-methoxynaphthalen-2-yl)(thiazol-5-yl)methanol (2.0 g) was dissolvedin dichloromethane (30 ml). To the solution was added manganese dioxide(6.0 g), and the mixture was stirred at room temperature for 3 h. Themixture was filtered with celite and the cake was rinsed withdichloromethane. The filtrate was concentrated and the obtained residuewas recrystallized from ethyl acetate to give the titled compound (1.71g) as a pale yellow powder.

¹H-NMR (CDCl₃) δ: 3.98 (3H, s), 7.21–7.28 (2H, m), 7.87 (1H, dd, J=3.2,8.6 Hz), 7.97 (1H, dd, J=1.7, 8.7 Hz), 8.38 (1H, s), 8.46 (1H, s), 9.09(1H, s).

IR (KBr): 1624, 1481, 1306, 1265, 1217, 862, 816 cm⁻¹.

(iii) Production of1-(6-methoxynaphthalen-2-yl)-1-(thiazol-5-yl)-1-propanol

In a similar manner to that described in Example 1-(iv), a reaction wascarried out by using (6-methoxynaphthalen-2-yl) (thiazol-5-yl)ketone(800 mg) to give the titled compound (447 mg) as a yellow substance.

¹H-NMR (CDCl₃) δ: 0.86 (3H, d, J=6.8 Hz), 1.05 (3H, d, J=6.8 Hz),2.70–2.87 (2H, m), 3.91 (3H, s), 7.10–7.17 (2H, m), 7.50 (1H, dd, J=1.9,8.7 Hz), 7.69 (1H, d, J=8.6 Hz), 7.73 (1H, d, J=8.8 Hz), 7.83 (1H, s),7.93 (1H, d, J=1.8 Hz), 8.66 (1H, s).

IR (KBr): 3187, 2971, 1402, 1269, 1144, 1026, 887, 843, 799 cm⁻¹.

EXAMPLE 66 Production of1-(1H-imidazol-4-yl)-2-methyl-1-(6-propylnaphthalen-2-yl)-1-propanol

(i) Production of1-(6-Allylnaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

1-(6-Bromonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(2.0 g), allyltributyltin (1.26 ml),tris(dibenzylideneacetone)dipalladium (92 mg), tri(2-furyl)phosphine (79mg) and lithium chloride (432 mg) were dissolved in DMF (20 ml). Thesolution was stirred at 80° C. for 9 h. The solution was cooled, anddiluted with water. The mixture was extracted with ethyl acetate, washedwith water and saturated sodium chloride solution, successively, anddried. The solvent was distilled off and the residue was purified bysilica gel chromatography (eluent, hexane:THF=6:1) followed bycrystallization from isopropyl ether-hexane to give the titled compound(1.57 g) as colorless needles.

¹H-NMR (CDCl₃) δ: 0.74 (3H, d, J=6.7 Hz), 0.95 (3H, d, J=6.7 Hz),2.46–2.60 (1H, m), 3.53 (2H, d, J=6.6 Hz), 3.71 (1H, s), 5.07–5.18 (2H,m), 6.04 (1H, ddt, J=3.3, 10.1, 16.9 Hz), 6.80 (1H, d, J=1.4 Hz),7.10–7.18 (6H, m), 7.27–7.36 (11H, m), 7.54 (1H, dd, J=1.8, 8.6 Hz),7.57 (1H, s), 7.66–7.78 (2H, m), 7.99 (1H, d, J=1.4 Hz).

IR (KBr): 3214, 2969, 1493, 1445, 1015, 907, 816, 748, 700 cm⁻¹.

(ii) Production of2-methyl-1-(6-propylnaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

1-(6-Allylnaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.40 g) was dissolved in THF-methanol (1:2)(15 ml). To the solution wasadded 10% palladium carbon (140 mg), and the mixture was stirred at roomtemperature for 2 h under hydrogen atmosphere. The catalyst was filteredand washed with THF. The filtrate was concentrated. The residue waschromatographed on silica gel (eluent, hexane:THF=1:1) and crystallizedfrom isopropyl ether-hexane to give the titled compound (1.28 g) as acolorless powder.

¹H-NMR (CDCl₃) δ: 0.74 (3H, d, J=6.8 Hz), 0.93–1.00 (6H, m), 1.66–1.81(2H, m), 2.47–2.60 (1H, m), 2.69–2.76 (2H, m), 3.75 (1H, s), 7.80 (1H,d, J=1.4 Hz), 7.10–7.18 (6H, m), 7.27–7.36 (11H, m), 7.53 (1H, dd,J=1.8, 8.6 Hz), 7.55 (1H, s), 7.66–7.74 (2H, m), 7.98 (1H, s).

IR (KBr): 3486, 2963, 1493, 1443, 1159, 1007, 818, 756, 747, 702 cm⁻¹.

(iii) Production of1-(1H-imidazol-4-yl)-2-methyl-1-(6-propylnaphthalen-2-yl)-1-propanol

In a similar manner to that described in Example 50-(ii), a reaction wascarried out by using2-methyl-1-(6-propylnaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.10 g) to give the titled compound (506 mg) as a colorless powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.81 (3H, d, J=6.7 Hz), 0.97 (3H, t, J=7.3 Hz),1.01 (3H, d, J=6.7 Hz), 1.63–1.81 (2H, m), 2.66–2.80 (3H, m), 6.99 (1H,d, J=1.0 Hz), 7.31 (1H, dd, J=1.7, 8.3 Hz), 7.50–7.57 (2H, m), 7.68–7.77(2H, m), 7.95 (1H, m).

IR (KBr): 3169, 2965, 1464, 1435, 1121, 1028, 951, 901, 816 cm⁻¹.

EXAMPLE 67 Production of1-(1H-imidazol-4-yl)-1-(6-isopropylnaphthalen-2-yl)-2-methyl-1-propanol

(i) Production of1-(6-isopropenylnaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

To a solution of methyltriphenylphosphonium bromide (3.24 g) in THF (80ml) was added potassium t-butoxide (1.02 g) under ice cooling, and themixture was stirred for 5 min. To the mixture was added a solution of1-[6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]naphthalen-2-yl]-1-ethanone(2.0 g) in THF (40 ml), and the mixture was stirred at room temperature.After 30 min, to the mixture was added a mixed solution ofmethyltriphenylphosphonium bromide (1.30 g) and potassium t-butoxide(407 mg) in THF (15 ml), and the mixture was stirred at room temperaturefor 30 min. The mixture was diluted with water, extracted with ethylacetate, washed with saturated sodium chloride solution and dried. Thesolvent was distilled off, and the residue was purified by silica gelchromatography (eluent, hexane:THF=6:1) to give the titled compound(1.91 g) as a colorless powder.

¹H-NMR (CDCl₃) δ: 0.74 (3H, d, J=6.8 Hz), 0.94 (3H, d, J=6.8 Hz), 2.25(3H, s), 2.47–2.2.60 (1H, m), 3.71 (1H, br s), 5.16 (1H, m), 5.50 (1H,s), 6.80 (1H, d, J=1.4 Hz), 7.08–7.7.18 (6H, m), 7.29–7.37 (10H, m),7.55 (1H, dd, J=1.8, 8.6 Hz), 7.63 (1H, d, J=1.8, 8.6 Hz), 7.71–7.80(3H, m), 7.98 (1H, s).

IR (KBr): 3193, 1493, 1445, 1144, 1017, 891, 748, 702 cm⁻¹.

(ii) Production of1-(6-isopropylnaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

1-(6-Isopropenylnaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.70 g) was dissolved in THF-methanol (2:1) (12 ml). To the solutionwere added 10% palladium carbon (170 mg), and the mixture was stirred atroom temperature for 2 h under hydrogen atmosphere. The catalyst wasfiltered and washed with THF. The filtrate was concentrated and theobtained residue was purified by silica gel chromatography (eluent,hexane:THF=1:1). Crystallization from isopropyl ether-hexane gave thetitled compound (1.60 g) as a colorless powder.

¹H-NMR (CDCl₃) δ: 0.74 (3H, d, J=6.7 Hz), 0.95 (3H, d, J=6.7 Hz), 1.33(6H, d, J=6.8 Hz), 2.47–2.60 (1H, m), 2.98–3.12 (1H, m), 3.69 (1H, s),6.80 (1H, d, J=1.4 Hz), 7.10–7.15 (6H, m), 7.30–7.38 (11H, m), 7.53 (1H,d, J=1.8, 8.6 Hz), 7.59 (1H, s), 7.68–7.77 (2H, m), 7.98 (1H, s).

IR (KBr): 3210, 2965, 1491, 1445, 1167, 1015, 907, 820, 756, 747, 700cm⁻¹.

(iii) Production of1-(1H-imidazol-4-yl)-2-methyl-1-[6-(2-propyl)naphthalen-2-yl]-1-propanol

In a similar manner to that described in Example 50-(ii), a reaction wascarried out by using1-(6-isopropylnaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.40 g) to give the titled compound (665 mg) as a colorless powder.

¹H-NMR (CDCl₃) δ: 0.79 (3H, d, J=6.7 Hz), 1.00 (3H, d, J=6.7 Hz), 1.32(6H, d, J=7.0 Hz), 2.62–2.75 (1H, m), 2.97–3.11 (1H, m), 4.75 (2H, brs), 6.93 (1H, d, J=1.0 Hz), 7.36 (1H, dd, J=1.7, 8.7 Hz), 7.42 (1H, d,J=1.0 Hz), 7.55 (1H, dd, J=1.8, 8.6 Hz), 7.59 (1H, s), 7.69–7.77 (2H,m), 7.99 (1H, s).

IR (KBr): 3054, 2961, 1462, 1385, 1163, 1130, 1003, 887, 818 cm⁻¹.

Preparation 1

Capsules

(1) Compound obtained in Example 2 10 mg

(2) lactose 90 mg

(3) microcrystalline cellulose 70 mg

(4) magnesium stearate 10 mg

One capsule 180 mg

The above (1), (2) and (3) and 5 mg of (4) were mixed. The mixture wasgranulated. To the granules was added (4) remaining. The whole contentwas sealed in a capsule.

Preparation 2

Tablets

(1) Compound obtained in Example 1 10 mg

(2) lactose 35 mg

(3) corn starch 150 mg

(4) microcrystalline cellulose 30 mg

(5) magnesium stearate 5 mg

One Tablet 230 mg

The above (1), (2), (3), 20 mg of (4) and 2.5 mg of (5) were mixed. Themixture was granulated. To the granules was added (4) remaining and (5)remaining, and the mixture was compressively molded to give a tablet.

Experiment 1

Assay of Inhibitory Activity on Rat Steroid C_(17,20)-Lyase in Vitro

Inhibitory activity was determined according to the method described inThe Prostate, vol. 26, 140–150 (1995) with some modifications.

Testes excised from 13-week old, male SD rats were homogenized, andtesticular microsomes were prepared by a series of centrifugation. Themicrosome protein (7 μg/10 μl) was added to 10 μl of 100 mM phosphatebuffer (pH 7.4) in which 10 nM (final concentration)[1,2-3H]-17-α-hydroxyprogesterone, NADPH, and test compounds weredissolved. The reaction mixture was incubated for 7 min at 37° C.,terminated by addition of 40 μl of Ethyl acetate, and brieflycentrifuged. The substrate and the products (testosterone andandrostenedione) in the upper phase were separated by silica gel thinlayer chromatography. Detection of the spots and measurement of theradioactivity were performed by a BAS 2000 Bioimage analyzer. Theconcentration of the test compounds necessary to reduce theconcentration of the products by 50% (The concentration in the controlgroup in which no test compound was added was taken as 100%) wascalculated, and shown in Table 1.

TABLE 1 IC₅₀ Example Test Compound (nM) 1

33 4

64 9

32 11

32 12

41 19

35Experiment 2Assay of Inhibitory Activity on Testosterone Biosynthesis in Rats

Test compounds were orally administered to 9-week old, male SD(Sprague-Dawley) rats at a dose of 50 mg/kg. Two-h later blood was takenand testosterone concentration in serum was measured byradioimmunoassay. The percentage of the testosterone concentration ofthe groups of rats, which received test compounds, to that of thecontrol group was calculated, and regarded as the inhibitory activity.

TABLE 2 Inhibitory activity on Test testosterone Com- biosynthesis pound(T/C, %) Exam-ple 1

2.0 Exam-ple 11

9.0 Exam-ple 12

10

INDUSTRIAL APPLICABILITY

The compounds of the present invention and salts thereof have aninhibitory activity of steroid C_(17,20)-lyase and are useful forpreventing and treating a mammal suffering from, for example, primarytumor, its metastasis and recurrence thereof, and various symptomsaccompanied with these cancer, various diseases such as prostatichypertrophy, virilism, hirsutism, male pattern alopecia, precociouspuberty, endometriosis, uterus myoma, mastopathy, polycystic ovarysyndrome, etc.

1. A compound of the formula:

wherein A¹ is a pyridyl group, which may be substituted with 1) aC₁₋₄alkyl group unsubstituted or substituted with a C₁₋₄alkanoyl,carboxyl, or a C₁₋₄alkoxy-carbonyl, 2) a C₁₋₃alkoxy group, 3)C₁₋₆alkanoyl, 4) C₁₋₄alkylsulfonyl, 5) carbamoyl, a mono- ordi-C₁₋₁₀alkyl carbamoyl group, a mono- or di-C₆₋₁₄arylcarbamoyl group ora mono- or di-C₇₋₁₆aralkylcarbamoyl group, or 6) sulfamoyl, a mono- ordi-C₁₋₁₀alkyl sulfamoyl group, a mono- or di-C₆₋₁₄arylsulfamoyl group,or a mono- or di-C₇₋₁₆aralkyl sulfamoyl group; R¹¹ is a hydrogen atom, ahydrocarbon group which may be substituted; or a monocyclic aromaticheterocyclic group which may be substituted; R²¹ is a hydrogen atom or alower alkyl group which may be substituted; R³, R⁴, R⁵, R⁶, R⁷, R⁸ andR⁹ are independently a hydrogen atom, a hydrocarbon group which may besubstituted, a hydroxy group which may be substituted, a thiol groupwhich may be substituted, an amino group which may be substituted, anacyl group or a halogen atom, provided (1) that R⁷ is a hydroxy groupwhich may be substituted or a lower alkyl group when A¹ is a pyridylgroup and one of R¹¹ or R²¹ is a hydrogen atom and (2) that R²¹ is alower alkyl group which may be substituted when R¹¹ is a hydrogen atom,or a salt thereof.
 2. A compound as claimed in claim 1, wherein R³, R⁴,R⁵, R⁶, R⁷, R⁸ and R⁹ are independently a hydrogen atom, a hydrocarbongroup which may be substituted, a hydroxy group which may besubstituted, an amino group which may be substituted, an acyl group or ahalogen atom.
 3. A compound as claimed in claim 1, wherein R³, R⁴, R⁵,R⁶, R⁷, R⁸ and R⁹ are independently a hydrogen atom, a hydrocarbon groupwhich may be substituted, a hydroxy group which may be substituted or anacyl group.
 4. A compound as claimed in claim 1, wherein R³, R⁴, R⁵, R⁶,R⁷, R⁸ and R⁹ are independently a hydrogen atom, a hydrocarbon groupwhich may be substituted, a hydroxy group which may be substituted, or ahalogen atom.
 5. A compound as claimed in claim 1, wherein A¹ is a 3-or4-pyridyl group which may be substituted with 1) a C₁₋₄alkyl groupunsubstituted or substituted with a C₁₋₄alkanoyl, carboxyl, or aC₁₋₄alkoxy-carbonyl, 2) a C₁₋₃alkoxy group, 3) C₁₋₆alkanoyl, 4)C₁₋₄alkylsulfonyl, 5) carbamoyl, a mono- or di-C₁₋₁₀alkyl carbamoylgroup, a mono- or di-C₆₋₁₄arylcarbamoyl group or a mono- ordi-C₇₋₁₆aralkylcarbamoyl group, or 6) sulfamoyl, a mono- ordi-C₁₋₁₀alkyl sulfamoyl group, a mono- or di-C₆₋₁₄arylsulfamoyl group,or a mono- or di-C₇₋₁₆aralkyl sulfamoyl group.
 6. A compound as claimedin claim 1, wherein R²¹ is a hydrogen atom or a lower alkyl group.
 7. Acompound as claimed in claim 1, wherein R²¹ is a hydrogen atom.
 8. Acompound as claimed in claim 1, wherein one to three groups selectedfrom a group consisting of R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ areindependently a hydrocarbon group which may be substituted, a hydroxygroup which may be substituted, an amino group which may be substituted,an acyl group or a halogen atom.
 9. A compound as claimed in claim 1,wherein one to three groups selected from a group consisting of R³, R⁴,R⁵, R⁶, R⁷, R⁸ and R⁹ are independently a lower(C₁₋₆) alkyl group whichmay be substituted, a hydroxy group which may be substituted or aC₁₋₆acyl group.
 10. A compound as claimed in claim 1, wherein R¹¹ is ahydrogen atom, a lower alkyl group which may be substituted, a phenylgroup which may be substituted or a pyridyl group which may besubstituted.
 11. A compound as claimed in claim 1, wherein R¹¹ is ahydrogen atom, a lower alkenyl group, a cyclic alkyl group, a phenylgroup, a pyridyl group, or a lower alkyl group which may be substitutedwith halogen atom(s).
 12. A compound as claimed in claim 1, wherein R¹¹is an C₁₋₆alkyl group and R²¹ is a hydrogen atom.
 13. A compound asclaimed in claim 1, wherein R¹¹ is an isopropyl group and R²¹ is ahydrogen atom.
 14. A compound as claimed in claim 1, wherein R⁷ is ahydroxy group which may be substituted or a lower alkyl group.
 15. Acompound as claimed in claim 1, wherein R⁷ is (1) a hydroxy group whichmay be substituted with a lower alkanoyl group, a loweralkanoyloxy-lower alkyl group, a lower alkyl group, a lower alkoxy-loweralkyl group, a lower alkyl group which may have one to 4 fluorine atoms,or a benzyl group, (2) a halogen atom, (3) a lower alkyl group which maybe substituted with a hydroxy group, (4) a lower alkynyl group, (5) alower alkanoyl group, (6) an amino group which may be substituted with alower alkanoyl group, a lower alkylaminocarbonyl group or a loweralkylsulfonyl group, or (7) a lower alkylthio group.
 16. A compound asclaimed in claim 1, wherein R⁷ is a lower alkyl group, a lower alkoxygroup or a lower alkanoylamino group.
 17. A compound as claimed in claim1, wherein R⁷ is a methoxy group.
 18. A compound as claimed in claim 1,wherein R⁸ is a hydrogen atom, a lower alkyl group or a lower alkoxygroup.
 19. A compound as claimed in claim 1, wherein R⁸ is a hydrogenatom or a lower alkoxy group.
 20. A compound as claimed in claim 1,wherein R⁶ is (1) a hydrogen atom, (2) a halogen atom, (3) a loweralkoxy group or (4) a lower alkyl group which may be substituted with ahydroxy group.
 21. A compound as claimed in claim 1, wherein R⁶ is ahydrogen atom or a lower alkyl group.
 22. A compound as claimed in claim1, wherein one of R⁶, R⁷ and R⁸ is a lower alkyl group or a lower alkoxygroup.
 23. A compound as claimed in claim 1, wherein each of R³, R⁴, R⁵and R⁹ is a hydrogen atom.
 24. A prodrug of a compound as claimed inclaim
 1. 25. A pharmaceutical composition containing a compound claimedin claim 1 or a prodrug thereof.
 26. A steroid C_(17,20)-lyaseinhibitory composition containing a compound of the formula:

wherein A is a nitrogen-containing heterocyclic group which may besubstituted, R¹ is a hydrogen atom, hydrocarbon group which may besubstituted, or monocyclic aromatic heterocyclic group which may besubstituted, R² is a hydrogen atom or a lower alkyl group which may besubstituted, R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are independently a hydrogenatom, a hydrocarbon group which may be substituted, a hydroxy groupwhich may be substituted, a thiol group which may be substituted, anamino group which may be substituted, an acyl group or a halogen atom, asalt thereof or a prodrug thereof.
 27. A composition as claimed in claim26, which is an antitumor agent for treating breast cancer or prostratecancer.